id: P51671
gene_symbol: CCL11
product_type: PROTEIN
status: COMPLETE
taxon:
  id: NCBITaxon:9606
  label: Homo sapiens
description: >-
  CCL11 (also known as Eotaxin-1) is a secreted CC chemokine that functions as a potent
  and selective chemoattractant for eosinophils. It signals primarily through the
  G-protein-coupled receptor CCR3, inducing directed cell migration (chemotaxis),
  cytoskeletal rearrangement, calcium mobilization, and activation of downstream
  MAP kinase cascades (ERK2, p38). CCL11 is produced by fibroblasts, epithelial cells,
  endothelial cells, macrophages, and eosinophils themselves, and is induced by
  pro-inflammatory cytokines (TNF-alpha, IL-1alpha, IFN-gamma) and type-2 cytokines
  (IL-4, IL-13). Beyond eosinophil recruitment in allergic inflammation (asthma, atopic
  dermatitis), CCL11 also promotes endothelial cell proliferation and migration via
  CCR3 in the context of choroidal neovascularization, and has been implicated in
  neuroinflammation and cognitive decline via CCR3 signaling on microglia. The mature
  protein is 74 amino acids (after signal peptide cleavage), adopts a typical chemokine
  fold with a 3-stranded beta-sheet and overlying alpha-helix, and can exist in
  monomer-dimer equilibrium. It is O-glycosylated at Thr-94.
existing_annotations:
  - term:
      id: GO:0005615
      label: extracellular space
    evidence_type: IBA
    original_reference_id: GO_REF:0000033
    review:
      summary: >-
        CCL11/Eotaxin is a secreted chemokine that functions in the extracellular
        space. UniProt annotates it as "Secreted" (PubMed:8597956). The IBA annotation
        is consistent with phylogenetic inference across the CC chemokine family.
      action: ACCEPT
      reason: >-
        CCL11 is a secreted protein that acts extracellularly to create chemotactic
        gradients. This is well-established and consistent with the signal peptide
        (residues 1-23) and its function as a soluble ligand for CCR3.
      supported_by:
        - reference_id: PMID:8597956
          supporting_text: "Human eotaxin is a specific chemoattractant for eosinophil cells and provides a new mechanism to explain tissue eosinophilia."

  - term:
      id: GO:0008009
      label: chemokine activity
    evidence_type: IBA
    original_reference_id: GO_REF:0000033
    review:
      summary: >-
        Chemokine activity is the core molecular function of CCL11. It acts as a
        chemoattractant primarily for eosinophils via CCR3 (PMID:8631813, PMID:10072545).
        The IBA annotation is phylogenetically sound across CC chemokines.
      action: ACCEPT
      reason: >-
        CCL11 is definitively a chemokine. Its primary molecular function is to act
        as a chemoattractant ligand, signaling through CCR3 to induce directed cell
        migration. This is its canonical and core function.
      supported_by:
        - reference_id: PMID:10072545
          supporting_text: "Those chemokines acting on CCR3 induced a rapid shape change in eosinophils from all donors; of these, eotaxin and eotaxin-2 were the most potent."

  - term:
      id: GO:0070098
      label: chemokine-mediated signaling pathway
    evidence_type: IBA
    original_reference_id: GO_REF:0000033
    review:
      summary: >-
        CCL11 is a chemokine ligand that initiates chemokine-mediated signaling through
        CCR3. This is directly supported by multiple studies showing CCL11 binding to
        CCR3 triggers downstream signaling cascades including MAP kinase activation
        (PMID:10706854) and calcium mobilization (PMID:10415069).
      action: ACCEPT
      reason: >-
        As a chemokine, CCL11 inherently participates in chemokine-mediated signaling
        pathways by binding and activating its receptor CCR3. This is a core function.
      supported_by:
        - reference_id: PMID:10706854
          supporting_text: "Eotaxin and other CC chemokines acting via CC chemokine receptor-3 (CCR3) are believed to play an integral role in the development of eosinophilic inflammation in asthma and allergic inflammatory diseases."

  - term:
      id: GO:0061844
      label: antimicrobial humoral immune response mediated by antimicrobial peptide
    evidence_type: IBA
    original_reference_id: GO_REF:0000033
    review:
      summary: >-
        This IBA annotation is propagated from the broader CC chemokine family. While
        some chemokines have direct antimicrobial peptide activity, CCL11/Eotaxin is
        primarily characterized as an eosinophil chemoattractant rather than a direct
        antimicrobial peptide. The evidence for direct antimicrobial activity of CCL11
        specifically is limited.
      action: KEEP_AS_NON_CORE
      reason: >-
        While the IBA annotation reflects a phylogenetically-inferred function shared
        across CC chemokines, CCL11 is not primarily known for direct antimicrobial
        peptide activity. Its core function is eosinophil chemotaxis. Some CC chemokines
        do have antimicrobial properties, and this may apply to CCL11 as well, but it
        is not a core function.

  - term:
      id: GO:0048245
      label: eosinophil chemotaxis
    evidence_type: IBA
    original_reference_id: GO_REF:0000033
    review:
      summary: >-
        Eosinophil chemotaxis is the canonical and best-characterized biological
        process of CCL11/Eotaxin. It was originally cloned as a specific eosinophil
        chemoattractant (PMID:8597956, PMID:8631813). The IBA annotation reinforces
        this across species.
      action: ACCEPT
      reason: >-
        This is arguably the single most defining function of CCL11. It was named
        "eotaxin" specifically for its eosinophil-selective chemotactic activity.
      supported_by:
        - reference_id: PMID:10072545
          supporting_text: "Those chemokines acting on CCR3 induced a rapid shape change in eosinophils from all donors; of these, eotaxin and eotaxin-2 were the most potent."

  - term:
      id: GO:0030335
      label: positive regulation of cell migration
    evidence_type: IBA
    original_reference_id: GO_REF:0000033
    review:
      summary: >-
        CCL11 promotes cell migration in multiple cell types. It induces eosinophil
        chemotaxis (PMID:10072545), endothelial cell migration (PMID:19525930), and
        FLS/monocyte migration (PMID:33846499). The IBA annotation is well-supported.
      action: ACCEPT
      reason: >-
        As a chemokine, positive regulation of cell migration is a core function of
        CCL11. This is supported by extensive experimental evidence across multiple
        cell types and contexts.
      supported_by:
        - reference_id: PMID:19525930
          supporting_text: "All three eotaxins also activated Rac-1 (Supplementary Fig. S3), a small GTPase that is critical in regulating endothelial cell spreading and migration, and promoted human CEC migration in a dose-dependent fashion (Fig. 2f)."

  - term:
      id: GO:0006954
      label: inflammatory response
    evidence_type: IBA
    original_reference_id: GO_REF:0000033
    review:
      summary: >-
        CCL11 is a pro-inflammatory chemokine that plays a central role in allergic
        inflammatory responses by recruiting eosinophils to sites of inflammation.
        This is well-established across multiple disease contexts including asthma
        and atopic dermatitis.
      action: ACCEPT
      reason: >-
        Involvement in inflammatory response is a core function of CCL11. It mediates
        eosinophil recruitment in type-2/allergic inflammation, which is its primary
        physiological role.
      supported_by:
        - reference_id: PMID:10708591
          supporting_text: "Eotaxin is an eosinophil-specific C-C chemokine that is implicated in the pathogenesis of eosinophilic inflammatory diseases, such as asthma and atopic dermatitis, by acting specifically on its receptor CCR3."

  - term:
      id: GO:0048020
      label: CCR chemokine receptor binding
    evidence_type: IBA
    original_reference_id: GO_REF:0000033
    review:
      summary: >-
        CCL11 binds CCR3 as its primary receptor (PMID:8631813). It can also interact
        with CCR5 and has controversial/partial activity at CCR2. The IBA annotation
        for CCR chemokine receptor binding is well-supported.
      action: ACCEPT
      reason: >-
        CCR chemokine receptor binding is a core molecular function of CCL11. It binds
        CCR3 with high affinity as its principal receptor. This is the parent term that
        encompasses the more specific CCR3 binding, which is also annotated.
      supported_by:
        - reference_id: PMID:9712872
          supporting_text: "The solution structure of the CCR3-specific chemokine, eotaxin, has been determined by NMR spectroscopy."

  - term:
      id: GO:0005125
      label: cytokine activity
    evidence_type: IEA
    original_reference_id: GO_REF:0000043
    review:
      summary: >-
        CCL11 is classified as a cytokine (specifically a chemokine, which is a
        subclass of cytokines). The IEA annotation from UniProt keyword mapping is
        correct but less specific than the chemokine activity annotation.
      action: ACCEPT
      reason: >-
        Cytokine activity is a parent term of chemokine activity. While less specific,
        it is not incorrect. The more specific chemokine activity term is also present.
        Acceptable as a broader IEA annotation.

  - term:
      id: GO:0005576
      label: extracellular region
    evidence_type: IEA
    original_reference_id: GO_REF:0000120
    review:
      summary: >-
        CCL11 is a secreted protein that localizes to the extracellular region.
        This IEA annotation is consistent with domain-based predictions and the
        established biology of chemokines.
      action: ACCEPT
      reason: >-
        Extracellular region is a broader parent of extracellular space. Both are
        correct for this secreted chemokine. The IEA annotation is consistent with
        multiple higher-evidence annotations.

  - term:
      id: GO:0005615
      label: extracellular space
    evidence_type: IEA
    original_reference_id: GO_REF:0000120
    review:
      summary: >-
        Duplicate of the IBA annotation for the same term. CCL11 is secreted and
        acts in the extracellular space. This IEA annotation is redundant with
        the IBA annotation but not incorrect.
      action: ACCEPT
      reason: >-
        Correct localization for a secreted chemokine. Redundant with IBA but
        acceptable as independent evidence.

  - term:
      id: GO:0006935
      label: chemotaxis
    evidence_type: IEA
    original_reference_id: GO_REF:0000043
    review:
      summary: >-
        CCL11 is a chemotactic factor. The IEA annotation from UniProt keyword
        mapping to chemotaxis is correct. More specific terms (eosinophil chemotaxis)
        are also annotated.
      action: ACCEPT
      reason: >-
        Chemotaxis is a core biological process for CCL11. This broader term is
        acceptable alongside the more specific eosinophil chemotaxis annotation.

  - term:
      id: GO:0006954
      label: inflammatory response
    evidence_type: IEA
    original_reference_id: GO_REF:0000043
    review:
      summary: >-
        Duplicate of the IBA annotation for inflammatory response. CCL11 is clearly
        involved in inflammatory responses. The IEA from keyword mapping is redundant
        but correct.
      action: ACCEPT
      reason: >-
        Correct annotation, redundant with IBA annotation for the same term.

  - term:
      id: GO:0006955
      label: immune response
    evidence_type: IEA
    original_reference_id: GO_REF:0000002
    review:
      summary: >-
        CCL11 participates in immune responses by recruiting eosinophils and other
        immune cells. The IEA annotation from InterPro domain mapping is correct
        but very broad.
      action: ACCEPT
      reason: >-
        Immune response is a broad parent term. While it is less informative than
        the more specific inflammatory response or eosinophil chemotaxis terms,
        it is not incorrect for this chemokine.

  - term:
      id: GO:0008009
      label: chemokine activity
    evidence_type: IEA
    original_reference_id: GO_REF:0000120
    review:
      summary: >-
        IEA annotation for chemokine activity, redundant with the IBA and IDA
        annotations for the same term. Correct.
      action: ACCEPT
      reason: >-
        Correct core molecular function. Redundant with higher-evidence annotations.

  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:18275857
    review:
      summary: >-
        This IPI annotation is from a study on dipeptidyl peptidase 8 (DPP8) substrates.
        The paper tested 27 chemokines for cleavage by DPP8, and CCL11 was among those
        surveyed but was NOT identified as a novel substrate of DPP8 (the novel substrates
        were IP10/CXCL10, ITAC/CXCL11, and SDF-1/CXCL12). The WITH column shows
        UniProtKB:P27487 (DPP4). This likely reflects a physical interaction detected
        by IntAct, but the term "protein binding" is uninformative.
      action: MODIFY
      reason: >-
        Protein binding is uninformative per curation guidelines. CCL11 can be
        processed by DPP4 (CD26) via N-terminal truncation, which is a well-known
        regulatory mechanism for chemokines. A more informative annotation would
        capture this as a substrate relationship. However, the interaction with DPP4
        is real and documented.
      proposed_replacement_terms:
        - id: GO:0005515
          label: protein binding
      additional_reference_ids:
        - PMID:18275857
      supported_by:
        - reference_id: PMID:18275857
          supporting_text: "N-terminal truncation of chemokines by proteases including dipeptidyl peptidase (DP) IV significantly alters their biological activity; generally ablating cognate G-protein coupled receptor engagement and often generating potent receptor antagonists."

  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:21314817
    review:
      summary: >-
        This IPI annotation from a study on fibroblast activation protein-alpha (FAP)
        substrates. The WITH column shows UniProtKB:P27487 (DPP4). The paper explicitly
        states that FAP showed negligible or no hydrolysis of chemokines that are
        readily hydrolysed by DPP4. This suggests the annotation reflects the
        CCL11-DPP4 interaction rather than CCL11-FAP interaction.
      action: MODIFY
      reason: >-
        Protein binding is uninformative per curation guidelines. The interaction
        with DPP4 is the relevant binding interaction here.
      proposed_replacement_terms:
        - id: GO:0005515
          label: protein binding
      supported_by:
        - reference_id: PMID:21314817
          supporting_text: "FAP showed negligible or no hydrolysis of eight chemokines that are readily hydrolysed by DPP4."

  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:23597562
    review:
      summary: >-
        This IPI annotation is from a study on a small-molecule FGF receptor blocker.
        The WITH column shows UniProtKB:P51677 (CCR3). This reflects the CCL11-CCR3
        physical interaction. While the paper itself is about FGF receptor inhibition,
        the IntAct interaction data likely captures the well-known CCL11-CCR3 binding.
      action: MODIFY
      reason: >-
        Protein binding is uninformative. The actual interaction is CCL11 binding to
        CCR3, which is already captured by the more specific CCR3 chemokine receptor
        binding annotation (GO:0031728). This protein binding annotation should be
        replaced with the more specific term.
      proposed_replacement_terms:
        - id: GO:0031728
          label: CCR3 chemokine receptor binding
      supported_by:
        - reference_id: PMID:23597562
          supporting_text: "Inhibition of tumor angiogenesis and growth by a small-molecule multi-FGF receptor blocker with allosteric properties."

  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:28381538
    review:
      summary: >-
        This IPI annotation is from the chemokine interactome mapping study by von
        Hundelshausen et al. (2017). The study systematically mapped chemokine-chemokine
        interactions using immunoligand blotting and surface plasmon resonance. CCL11
        was found to interact with multiple chemokines including CCL5/RANTES, PF4/CXCL4,
        CXCL10, CXCL12, CCL27, and CCL28. These are functionally relevant
        heteromeric interactions that can modulate chemokine activity.
      action: MODIFY
      reason: >-
        Protein binding is uninformative. The specific interactions documented in this
        study (chemokine-chemokine heterodimer formation) are biologically meaningful
        but "protein binding" does not capture this. A better term would reflect
        the chemokine-chemokine interaction specifically.
      proposed_replacement_terms:
        - id: GO:0048020
          label: CCR chemokine receptor binding
      supported_by:
        - reference_id: PMID:28381538
          supporting_text: "Heterophilic interactions between chemokines in a given microenvironment may amplify, inhibit, or modulate their activity; however, a systematic evaluation of the chemokine interactome has not been performed."

  - term:
      id: GO:0002544
      label: chronic inflammatory response
    evidence_type: IEA
    original_reference_id: GO_REF:0000107
    review:
      summary: >-
        IEA from Ensembl Compara ortholog transfer (rat Ccl11). CCL11 is involved
        in chronic inflammatory conditions such as asthma and atopic dermatitis.
        The annotation is plausible but represents a more specific inflammatory
        context.
      action: KEEP_AS_NON_CORE
      reason: >-
        CCL11 is involved in chronic inflammatory conditions (asthma, atopic dermatitis,
        RA), but this is a downstream consequence of its chemotactic function rather
        than a distinct core function. Keeping as non-core.

  - term:
      id: GO:0002551
      label: mast cell chemotaxis
    evidence_type: IEA
    original_reference_id: GO_REF:0000107
    review:
      summary: >-
        IEA from Ensembl Compara (rat ortholog). While CCR3 is expressed on mast
        cells and CCL11 can theoretically attract mast cells via CCR3, the primary
        evidence for CCL11 chemotactic activity is for eosinophils. In the AMD study
        (PMID:19525930), despite eotaxin expression, mast cells were NOT recruited,
        suggesting this function may be context-dependent.
      action: KEEP_AS_NON_CORE
      reason: >-
        While theoretically possible given CCR3 expression on mast cells, the evidence
        for CCL11-mediated mast cell chemotaxis is limited. In the AMD context
        (PMID:19525930), mast cells were not recruited despite eotaxin abundance.
        Eosinophil chemotaxis is the primary chemotactic function.
      supported_by:
        - reference_id: PMID:19525930
          supporting_text: "despite the expression of its ligands eotaxin-1, -2 and -3, neither eosinophils nor mast cells are present in human CNV."

  - term:
      id: GO:0007015
      label: actin filament organization
    evidence_type: IEA
    original_reference_id: GO_REF:0000107
    review:
      summary: >-
        IEA from Ensembl Compara (rat ortholog). CCL11 signaling through CCR3 induces
        cytoskeletal rearrangement including actin polymerization, as demonstrated
        in eosinophils (PMID:10072545) and endothelial cells (PMID:19525930). This is
        a downstream effect of chemokine signaling rather than a direct function of
        the ligand.
      action: KEEP_AS_NON_CORE
      reason: >-
        Actin filament organization occurs in responding cells as a consequence of
        CCR3 activation by CCL11, not as a direct biochemical function of the CCL11
        protein itself. This is a downstream cellular response to the chemokine signal.

  - term:
      id: GO:0007611
      label: learning or memory
    evidence_type: IEA
    original_reference_id: GO_REF:0000107
    review:
      summary: >-
        IEA from Ensembl Compara (mouse ortholog Ccl11, P48298). Recent reviews
        describe CCL11 as contributing to cognitive impairment by inhibiting
        neurogenesis, reducing synaptic density, and promoting neuronal cytotoxicity
        via CCR3 on microglia. However, this is a pleiotropic effect observed in
        aging contexts, not a core evolved function.
      action: KEEP_AS_NON_CORE
      reason: >-
        The link between CCL11 and learning/memory is based on aging studies in mice
        where elevated blood CCL11 impairs hippocampal neurogenesis and cognition.
        This is a pleiotropic pathological effect in aging rather than a core
        evolved function of the chemokine.

  - term:
      id: GO:0035962
      label: response to interleukin-13
    evidence_type: IEA
    original_reference_id: GO_REF:0000107
    review:
      summary: >-
        IEA from Ensembl Compara (rat ortholog). CCL11 expression is induced by
        IL-13 (a type-2 cytokine) in various cell types. This annotation likely
        reflects that CCL11 gene expression responds to IL-13 signaling, which is
        well-established in the context of type-2 inflammation.
      action: KEEP_AS_NON_CORE
      reason: >-
        This describes the regulation of CCL11 expression rather than a function
        of the CCL11 protein. CCL11 production is induced by IL-13, but this is
        about gene regulation, not protein function. Keep as non-core contextual
        information.

  - term:
      id: GO:0045766
      label: positive regulation of angiogenesis
    evidence_type: IEA
    original_reference_id: GO_REF:0000107
    review:
      summary: >-
        IEA from Ensembl Compara (mouse ortholog). CCL11 promotes angiogenesis through
        CCR3 on endothelial cells, as demonstrated in the AMD/choroidal neovascularization
        study (PMID:19525930). Eotaxins stimulated endothelial cell proliferation,
        actin polymerization, and migration. This is a well-supported non-core function.
      action: KEEP_AS_NON_CORE
      reason: >-
        While experimentally supported (PMID:19525930), positive regulation of
        angiogenesis is a secondary/pleiotropic function of CCL11 rather than its
        core evolved chemotactic function. It occurs in specific pathological contexts
        like AMD where CCR3 is expressed on neovascular endothelial cells.
      supported_by:
        - reference_id: PMID:19525930
          supporting_text: "each of the three eotaxins stimulated human CEC proliferation"

  - term:
      id: GO:0048245
      label: eosinophil chemotaxis
    evidence_type: IEA
    original_reference_id: GO_REF:0000107
    review:
      summary: >-
        IEA from Ensembl Compara (rat ortholog). Redundant with IBA and IDA
        annotations for the same term. Eosinophil chemotaxis is the core function
        of CCL11.
      action: ACCEPT
      reason: >-
        Correct core function. Redundant with higher-evidence annotations but
        independently derived from ortholog transfer.

  - term:
      id: GO:0050768
      label: negative regulation of neurogenesis
    evidence_type: IEA
    original_reference_id: GO_REF:0000107
    review:
      summary: >-
        IEA from Ensembl Compara (mouse ortholog). CCL11 has been shown to inhibit
        neurogenesis in mouse aging studies. This is a pleiotropic effect linked to
        aging rather than a core function.
      action: KEEP_AS_NON_CORE
      reason: >-
        Negative regulation of neurogenesis is a secondary/aging-related effect of
        CCL11 observed in mouse studies, not a core evolved function of this chemokine.

  - term:
      id: GO:0070371
      label: ERK1 and ERK2 cascade
    evidence_type: IEA
    original_reference_id: GO_REF:0000107
    review:
      summary: >-
        IEA from Ensembl Compara (rat ortholog). CCL11 activates ERK2 and p38 MAP
        kinases in eosinophils (PMID:10706854). This is a downstream signaling event
        triggered by CCR3 activation, not a direct function of CCL11 itself.
      action: KEEP_AS_NON_CORE
      reason: >-
        The ERK1/ERK2 cascade is activated downstream of CCR3 signaling upon CCL11
        binding. While experimentally demonstrated, this describes a downstream
        signaling consequence in the responding cell, not a direct function of the
        secreted chemokine ligand. The annotation is on the gene product that triggers
        the cascade as a ligand, which is a somewhat indirect relationship.
      supported_by:
        - reference_id: PMID:10706854
          supporting_text: "Eotaxin (10(-11) to 10(-7) mol/L) induced concentration-dependent phosphorylation of ERK2 and p38."

  - term:
      id: GO:0070670
      label: response to interleukin-4
    evidence_type: IEA
    original_reference_id: GO_REF:0000107
    review:
      summary: >-
        IEA from Ensembl Compara (rat ortholog). CCL11 expression is induced by IL-4
        signaling (via STAT6), which is well-established in the type-2 inflammation
        context. This annotation describes regulation of CCL11 gene expression rather
        than a function of the CCL11 protein.
      action: KEEP_AS_NON_CORE
      reason: >-
        This describes gene regulation (CCL11 expression is induced by IL-4) rather
        than a function of the CCL11 protein product. Keep as non-core contextual
        information.

  - term:
      id: GO:0060326
      label: cell chemotaxis
    evidence_type: IDA
    original_reference_id: PMID:33846499
    review:
      summary: >-
        IDA annotation from PMID:33846499 (Wakabayashi et al., 2021). This study
        demonstrated that CCL11 induces migration of RA fibroblast-like synoviocytes
        (FLS) and THP-1 monocytes in transwell migration assays. CCL11-stimulated
        FLS migrated significantly more than unstimulated cells, and CCL11 siRNA
        knockdown reduced FLS migration.
      action: ACCEPT
      reason: >-
        Cell chemotaxis is a core function of CCL11 as a chemokine. This study
        provides direct experimental evidence that CCL11 induces directed cell
        migration in multiple cell types beyond eosinophils, including fibroblast-like
        synoviocytes and monocytes.
      supported_by:
        - reference_id: PMID:33846499
          supporting_text: "CCL11-stimulated cells migrated significantly more efficiently than unstimulated cells (mean ± SEM, number of cells per field; 35.8 ± 5.2 and 24.5 ± 4.6, respectively, p < 0.05, Fig. 5A)"

  - term:
      id: GO:0070098
      label: chemokine-mediated signaling pathway
    evidence_type: IDA
    original_reference_id: PMID:19525930
    review:
      summary: >-
        IDA annotation from Takeda et al. (2009, Nature). The study demonstrated
        that CCL11 (eotaxin-1) activates CCR3-mediated signaling in choroidal
        endothelial cells, promoting proliferation, actin polymerization, Rac-1
        activation, and migration. This is direct evidence of CCL11 initiating
        chemokine-mediated signaling.
      action: ACCEPT
      reason: >-
        Well-supported by experimental evidence in the Nature paper. CCL11 binding
        to CCR3 activates downstream signaling cascades in endothelial cells,
        constituting chemokine-mediated signaling.
      supported_by:
        - reference_id: PMID:19525930
          supporting_text: "Stimulation of human CECs with any of the three eotaxins induced a rapid polymerization of actin molecules"

  - term:
      id: GO:0050768
      label: negative regulation of neurogenesis
    evidence_type: ISS
    original_reference_id: GO_REF:0000024
    review:
      summary: >-
        ISS annotation transferred from mouse ortholog (P48298). CCL11 has been
        shown to inhibit hippocampal neurogenesis in aging mouse studies. This is
        a pleiotropic effect related to aging/neuroinflammation rather than a core
        function.
      action: KEEP_AS_NON_CORE
      reason: >-
        Based on sequence similarity to mouse Ccl11 which was experimentally shown
        to inhibit neurogenesis. This is a pleiotropic aging-related effect, not a
        core evolved function. Redundant with IEA annotation.

  - term:
      id: GO:0007611
      label: learning or memory
    evidence_type: ISS
    original_reference_id: GO_REF:0000024
    review:
      summary: >-
        ISS annotation transferred from mouse ortholog (P48298). CCL11 affects
        learning and memory in mouse aging studies. This is a pleiotropic
        neuroinflammatory effect. Redundant with IEA annotation.
      action: KEEP_AS_NON_CORE
      reason: >-
        Pleiotropic aging-related effect transferred from mouse ortholog studies.
        Not a core evolved function of this chemokine.

  - term:
      id: GO:0046983
      label: protein dimerization activity
    evidence_type: IDA
    original_reference_id: PMID:9712872
    review:
      summary: >-
        IDA annotation from the NMR structural study by Crump et al. (1998). The
        study determined the solution structure of eotaxin and found it exists in
        equilibrium between monomer and dimer under a wide range of conditions. At
        pH <= 5 and low ionic strength, eotaxin was predominantly monomeric. This
        is a genuine biophysical property of the protein.
      action: ACCEPT
      reason: >-
        Protein dimerization is an experimentally demonstrated property of CCL11.
        Many CC chemokines form dimers, and this is likely biologically relevant
        for creating chemokine gradients and modulating activity.
      supported_by:
        - reference_id: PMID:9712872
          supporting_text: "The quaternary structure of eotaxin was investigated by ultracentrifugation and NMR, and it was found to be in equilibrium between monomer and dimer under a wide range of conditions."

  - term:
      id: GO:0031728
      label: CCR3 chemokine receptor binding
    evidence_type: IDA
    original_reference_id: PMID:11425309
    review:
      summary: >-
        IDA annotation from the eotaxin-3 structural study. Note that PMID:11425309
        is actually about eotaxin-3 (CCL26), not eotaxin-1 (CCL11). However, CCL11
        binding to CCR3 is very well established from multiple other studies
        (PMID:8631813, PMID:10072545). The reference may be incorrectly assigned
        but the annotation itself is correct.
      action: ACCEPT
      reason: >-
        CCR3 binding is the core molecular function of CCL11. While the specific
        reference (about eotaxin-3 structure) may not be the best citation for
        CCL11 specifically, the function is unambiguously correct and well-established
        from the original cloning papers (PMID:8631813).
      supported_by:
        - reference_id: PMID:9712872
          supporting_text: "The solution structure of the CCR3-specific chemokine, eotaxin, has been determined by NMR spectroscopy."

  - term:
      id: GO:0048018
      label: receptor ligand activity
    evidence_type: IDA
    original_reference_id: PMID:11425309
    review:
      summary: >-
        IDA annotation. CCL11 is a receptor ligand (for CCR3). This is a fundamental
        molecular function description -- CCL11 acts as a ligand that activates a
        receptor (CCR3 GPCR). While the reference is about eotaxin-3, the function
        is correct for CCL11.
      action: ACCEPT
      reason: >-
        Receptor ligand activity is a core molecular function of CCL11. It acts
        as a signaling ligand for the CCR3 G-protein coupled receptor.

  - term:
      id: GO:0005576
      label: extracellular region
    evidence_type: IDA
    original_reference_id: PMID:20041150
    review:
      summary: >-
        IDA annotation with reference to PMID:20041150, a paper about MEFV gene
        mutations in fibromyalgia. This paper measured CCL11 levels in plasma,
        demonstrating it is present in the extracellular region (blood). The
        annotation is correct for CCL11 localization.
      action: ACCEPT
      reason: >-
        CCL11 is a secreted protein found in the extracellular region. The reference
        measured CCL11 in plasma, confirming its extracellular localization. While
        the paper is primarily about MEFV, the detection of CCL11 in plasma supports
        the annotation.

  - term:
      id: GO:0007010
      label: cytoskeleton organization
    evidence_type: IDA
    original_reference_id: PMID:10072545
    review:
      summary: >-
        IDA annotation from Sabroe et al. (1999). The study showed that eotaxin
        induces leukocyte shape change mediated through rearrangements of the
        cellular cytoskeleton, essential for leukocyte migration. This is a
        downstream cellular response to CCL11/CCR3 signaling in responding cells.
      action: KEEP_AS_NON_CORE
      reason: >-
        Cytoskeleton organization in eosinophils is a downstream consequence of
        CCR3 activation by CCL11, not a direct function of the CCL11 protein.
        The ligand triggers cytoskeletal changes in the responding cell.
      supported_by:
        - reference_id: PMID:10072545
          supporting_text: "Leukocyte shape change responses are mediated through rearrangements of the cellular cytoskeleton in a dynamic process typically resulting in a polarized cell and are essential to the processes of leukocyte migration from the microcirculation into sites of inflammation."

  - term:
      id: GO:0008009
      label: chemokine activity
    evidence_type: IDA
    original_reference_id: PMID:10072545
    review:
      summary: >-
        IDA annotation from Sabroe et al. (1999). The study directly demonstrated
        that eotaxin acts as a chemokine by inducing rapid shape change and
        chemotactic responses in eosinophils via CCR3. This is direct experimental
        evidence for chemokine activity.
      action: ACCEPT
      reason: >-
        Core molecular function demonstrated by direct experimental evidence.
        Eotaxin was shown to be among the most potent CCR3-acting chemokines
        for eosinophil activation.
      supported_by:
        - reference_id: PMID:10072545
          supporting_text: "Those chemokines acting on CCR3 induced a rapid shape change in eosinophils from all donors; of these, eotaxin and eotaxin-2 were the most potent."

  - term:
      id: GO:0008360
      label: regulation of cell shape
    evidence_type: IDA
    original_reference_id: PMID:10072545
    review:
      summary: >-
        IDA annotation from Sabroe et al. (1999). CCL11 induces eosinophil shape
        change through cytoskeletal rearrangement. This is a downstream cellular
        response to CCR3 activation in responding cells.
      action: KEEP_AS_NON_CORE
      reason: >-
        Regulation of cell shape is a downstream consequence of CCR3 signaling
        in eosinophils. While experimentally demonstrated, it is not a core
        function of the CCL11 protein itself but rather a response in target cells.
      supported_by:
        - reference_id: PMID:10072545
          supporting_text: "Leukocyte shape change responses are mediated through rearrangements of the cellular cytoskeleton in a dynamic process typically resulting in a polarized cell"

  - term:
      id: GO:0048245
      label: eosinophil chemotaxis
    evidence_type: IDA
    original_reference_id: PMID:10072545
    review:
      summary: >-
        IDA annotation from Sabroe et al. (1999). Direct experimental demonstration
        that eotaxin induces eosinophil chemotaxis via CCR3. This is the core
        biological function of CCL11.
      action: ACCEPT
      reason: >-
        Core function of CCL11 directly demonstrated experimentally. Eotaxin
        is among the most potent eosinophil chemoattractants acting via CCR3.
      supported_by:
        - reference_id: PMID:10072545
          supporting_text: "Those chemokines acting on CCR3 induced a rapid shape change in eosinophils from all donors; of these, eotaxin and eotaxin-2 were the most potent."

  - term:
      id: GO:0001938
      label: positive regulation of endothelial cell proliferation
    evidence_type: IDA
    original_reference_id: PMID:19525930
    review:
      summary: >-
        IDA annotation from Takeda et al. (2009, Nature). The study showed that
        each of the three eotaxins (including CCL11) stimulated human choroidal
        endothelial cell (CEC) proliferation, and CCR3 neutralizing antibodies
        reduced CEC proliferation in vivo. This is a well-supported but non-core
        function in the context of choroidal neovascularization.
      action: KEEP_AS_NON_CORE
      reason: >-
        While experimentally well-supported in a high-impact publication, this
        function is specific to the pathological context of choroidal neovascularization
        in AMD, where CCR3 is aberrantly expressed on endothelial cells. It is not
        the core evolved function of CCL11.
      supported_by:
        - reference_id: PMID:19525930
          supporting_text: "each of the three eotaxins stimulated human CEC proliferation"

  - term:
      id: GO:0030335
      label: positive regulation of cell migration
    evidence_type: IDA
    original_reference_id: PMID:19525930
    review:
      summary: >-
        IDA annotation from Takeda et al. (2009). CCL11 promoted human CEC migration
        in a dose-dependent fashion, and activated Rac-1, a GTPase critical for
        endothelial cell spreading and migration. This reinforces the IBA annotation.
      action: ACCEPT
      reason: >-
        Positive regulation of cell migration is a core function of CCL11 as a
        chemokine. This IDA provides additional experimental evidence in endothelial
        cells beyond the eosinophil context.
      supported_by:
        - reference_id: PMID:19525930
          supporting_text: "All three eotaxins also activated Rac-1 (Supplementary Fig. S3), a small GTPase that is critical in regulating endothelial cell spreading and migration, and promoted human CEC migration in a dose-dependent fashion (Fig. 2f)."

  - term:
      id: GO:0030838
      label: positive regulation of actin filament polymerization
    evidence_type: IDA
    original_reference_id: PMID:19525930
    review:
      summary: >-
        IDA annotation from Takeda et al. (2009). Stimulation of human CECs with
        eotaxins induced rapid polymerization of actin molecules. This is a
        downstream cellular response to CCR3 signaling in endothelial cells.
      action: KEEP_AS_NON_CORE
      reason: >-
        Actin polymerization is a downstream cellular response in target cells
        following CCR3 activation by CCL11. It is not a direct function of the
        CCL11 protein itself but rather a consequence of its signaling activity.
      supported_by:
        - reference_id: PMID:19525930
          supporting_text: "Stimulation of human CECs with any of the three eotaxins induced a rapid polymerization of actin molecules"

  - term:
      id: GO:0005576
      label: extracellular region
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-443986
    review:
      summary: >-
        TAS annotation from Reactome pathway "Receptor ACKR2 binds most inflammatory
        CC chemokines". CCL11 is a secreted protein that binds to ACKR2 (a decoy
        chemokine receptor) in the extracellular region. This is consistent with
        its localization as a secreted chemokine.
      action: ACCEPT
      reason: >-
        Correct localization for a secreted chemokine, supported by Reactome pathway
        curation.

  - term:
      id: GO:0005576
      label: extracellular region
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-6793978
    review:
      summary: >-
        TAS annotation from Reactome pathway "Expression of STAT6-upregulated
        extracellular proteins". CCL11 is a STAT6-induced secreted protein, consistent
        with its regulation by IL-4/IL-13 signaling and extracellular localization.
      action: ACCEPT
      reason: >-
        Correct localization. CCL11 is a STAT6-regulated secreted protein.

  - term:
      id: GO:0006468
      label: protein phosphorylation
    evidence_type: TAS
    original_reference_id: PMID:10706854
    review:
      summary: >-
        TAS annotation citing Kampen et al. (2000). The paper shows that eotaxin
        induces phosphorylation of ERK2 and p38 in eosinophils. However, CCL11 is
        NOT a kinase -- it is a secreted chemokine ligand. The phosphorylation events
        are downstream signaling consequences in responding cells following CCR3
        activation. Annotating CCL11 with "protein phosphorylation" is misleading
        as it implies CCL11 catalyzes phosphorylation.
      action: MODIFY
      reason: >-
        CCL11 is a secreted chemokine with no kinase activity. The paper demonstrates
        that eotaxin-induced CCR3 signaling triggers phosphorylation of ERK2 and p38
        in eosinophils, but CCL11 does not directly catalyze phosphorylation. The
        annotation should be modified to reflect that CCL11 triggers signaling
        cascades in responding cells. A more appropriate annotation would capture the
        upstream signaling role.
      proposed_replacement_terms:
        - id: GO:0070098
          label: chemokine-mediated signaling pathway
      supported_by:
        - reference_id: PMID:10706854
          supporting_text: "Eotaxin (10(-11) to 10(-7) mol/L) induced concentration-dependent phosphorylation of ERK2 and p38. Phosphorylation was detectable after 30 seconds, peaked at about 1 minute, and returned to baseline after 2 to 5 minutes."

  - term:
      id: GO:0006874
      label: intracellular calcium ion homeostasis
    evidence_type: TAS
    original_reference_id: PMID:10415069
    review:
      summary: >-
        TAS annotation from Klein et al. (1999). The study showed that CCR3 on
        neurons responds to its chemokine ligands (including eotaxin/CCL11) with
        increases in intracellular calcium. However, calcium mobilization is a
        downstream signaling event in CCR3-expressing cells, not a direct function
        of the CCL11 ligand itself. Additionally, the term "homeostasis" is
        misleading -- CCL11 triggers transient calcium flux rather than maintaining
        calcium homeostasis.
      action: MARK_AS_OVER_ANNOTATED
      reason: >-
        Intracellular calcium ion homeostasis is a downstream signaling event in
        CCR3-expressing cells after CCL11 binding. CCL11 triggers transient calcium
        mobilization but does not maintain calcium homeostasis. This represents an
        over-annotation where a downstream response in target cells is attributed
        to the signaling ligand.
      supported_by:
        - reference_id: PMID:10415069
          supporting_text: "Chemokine receptors were shown to respond to their appropriate chemokine ligands with increases in intracellular calcium that, in the case of neurons, required predepolarization with KCl."

  - term:
      id: GO:0006935
      label: chemotaxis
    evidence_type: TAS
    original_reference_id: PMID:10706854
    review:
      summary: >-
        TAS annotation from Kampen et al. (2000). The study directly demonstrated
        eotaxin-induced eosinophil chemotaxis using Boyden microchambers and showed
        that MAP kinase inhibitors blocked this chemotaxis.
      action: ACCEPT
      reason: >-
        Chemotaxis is a core function of CCL11. This TAS annotation is well-supported
        by the referenced study and consistent with multiple other annotations.
      supported_by:
        - reference_id: PMID:10706854
          supporting_text: "We conclude that eotaxin induces a rapid concentration-dependent activation of ERK2 and p38 in eosinophils and that the activation of these MAP kinases is required for eotaxin-stimulated degranulation and directed locomotion."

  - term:
      id: GO:0006954
      label: inflammatory response
    evidence_type: TAS
    original_reference_id: PMID:10708591
    review:
      summary: >-
        TAS annotation from Huber et al. (2000). The paper describes induction of
        eotaxin and CCR3 by ionizing radiation and discusses CCL11 in the context
        of eosinophilic inflammatory diseases.
      action: ACCEPT
      reason: >-
        Inflammatory response is a core process for CCL11. The paper directly
        discusses CCL11 in the context of eosinophilic inflammatory pathogenesis.
      supported_by:
        - reference_id: PMID:10708591
          supporting_text: "Eotaxin is an eosinophil-specific C-C chemokine that is implicated in the pathogenesis of eosinophilic inflammatory diseases, such as asthma and atopic dermatitis, by acting specifically on its receptor CCR3."

  - term:
      id: GO:0007155
      label: cell adhesion
    evidence_type: TAS
    original_reference_id: PMID:10201960
    review:
      summary: >-
        TAS annotation from Jinquan et al. (1999). The study showed that eotaxin,
        in combination with IL-2 and IL-4, enhances expression of adhesion molecules
        (ICAM-1, CD29, CD49a, CD49b) on T lymphocytes and promotes adhesion and
        aggregation. However, the adhesion effect required prior IL-2/IL-4 stimulation
        to induce CCR3 expression on T cells and is an indirect consequence of
        chemokine signaling.
      action: KEEP_AS_NON_CORE
      reason: >-
        Cell adhesion promotion by CCL11 is context-dependent (requires IL-2/IL-4
        co-stimulation to induce CCR3 on T cells) and is a downstream consequence
        of CCR3 signaling rather than a direct adhesion function.
      supported_by:
        - reference_id: PMID:10201960
          supporting_text: "In combination with IL-2 and IL-4, eotaxin enhances the expression of adhesion molecules such as ICAM-1 and several integrins (CD29, CD49a, and CD49b) on T lymphocytes and thus promotes adhesion and aggregation of T lymphocytes."

  - term:
      id: GO:0007165
      label: signal transduction
    evidence_type: TAS
    original_reference_id: PMID:10706854
    review:
      summary: >-
        TAS annotation from Kampen et al. (2000). The study demonstrated that eotaxin
        induces signal transduction through CCR3, activating ERK2 and p38 MAP kinases.
        Signal transduction is a very broad term; more specific terms are available.
      action: ACCEPT
      reason: >-
        While very broad, signal transduction is correct for CCL11 as a signaling
        ligand that activates receptor-mediated signaling cascades. More specific
        terms (chemokine-mediated signaling pathway) are also annotated.

  - term:
      id: GO:0009314
      label: response to radiation
    evidence_type: TAS
    original_reference_id: PMID:10708591
    review:
      summary: >-
        TAS annotation from Huber et al. (2000). The paper showed that CCL11 (eotaxin)
        expression is upregulated by ionizing radiation in human dermal fibroblasts.
        This describes the regulation of CCL11 gene expression in response to radiation,
        not a function of the CCL11 protein.
      action: MARK_AS_OVER_ANNOTATED
      reason: >-
        This annotation describes the induction of CCL11 gene expression by ionizing
        radiation, not a function of the CCL11 protein itself. The CCL11 protein does
        not sense or respond to radiation; rather, its expression is upregulated by
        radiation in certain cell types. This is an annotation about gene regulation
        inappropriately applied to the gene product.
      supported_by:
        - reference_id: PMID:10708591
          supporting_text: "the expression of eotaxin is upregulated upon treatment with ionizing radiation (IR) in human dermal fibroblasts"

  - term:
      id: GO:0009615
      label: response to virus
    evidence_type: TAS
    original_reference_id: PMID:9558100
    review:
      summary: >-
        TAS annotation from Rubbert et al. (1998). The paper describes CCR3 as an HIV
        coreceptor on dendritic cells. CCR3 is identified as an eotaxin receptor on
        dendritic cells that may be used for HIV entry. However, this paper does not
        demonstrate a role for CCL11 in response to virus -- rather, it shows that
        the CCL11 receptor CCR3 can be exploited by HIV for cell entry. This is an
        over-annotation.
      action: MARK_AS_OVER_ANNOTATED
      reason: >-
        The cited paper describes CCR3 (the eotaxin receptor) as an HIV coreceptor
        on dendritic cells. This does not demonstrate that CCL11 protein itself
        participates in response to virus. The viral exploitation of CCR3 is a
        property of the receptor, not the chemokine ligand.
      supported_by:
        - reference_id: PMID:9558100
          supporting_text: "CCR3, the eotaxin receptor, initially identified on eosinophils, is expressed on DC and may be used as an entry coreceptor by certain dual-tropic strains."

core_functions:
  - molecular_function:
      id: GO:0008009
      label: chemokine activity
    description: >-
      CCL11 (Eotaxin-1) functions as a secreted CC chemokine that acts in the
      extracellular space as a potent and selective chemoattractant for eosinophils.
      This is its defining and canonical function. It was named "eotaxin" specifically
      for this eosinophil-selective chemotactic activity. CCL11 plays a central role
      in allergic/type-2 inflammatory responses by recruiting eosinophils to sites of
      inflammation, and is implicated in the pathogenesis of asthma, atopic dermatitis,
      eosinophilic esophagitis, and other eosinophilic inflammatory diseases.
    directly_involved_in:
      - id: GO:0048245
        label: eosinophil chemotaxis
      - id: GO:0006954
        label: inflammatory response
    locations:
      - id: GO:0005615
        label: extracellular space

  - molecular_function:
      id: GO:0031728
      label: CCR3 chemokine receptor binding
    description: >-
      CCL11 binds with high affinity to CCR3, a G-protein-coupled receptor expressed
      primarily on eosinophils, basophils, and certain other cell types. CCR3 binding
      is the molecular mechanism by which CCL11 exerts its chemotactic and signaling
      functions. Upon binding, CCR3 activates downstream signaling cascades including
      calcium mobilization, ERK2/p38 MAP kinase activation, and cytoskeletal
      rearrangement.
    directly_involved_in:
      - id: GO:0070098
        label: chemokine-mediated signaling pathway
    locations:
      - id: GO:0005615
        label: extracellular space

references:
  - id: GO_REF:0000002
    title: Gene Ontology annotation through association of InterPro records with GO terms
    findings: []
  - id: GO_REF:0000024
    title: Manual transfer of experimentally-verified manual GO annotation data to orthologs by curator judgment of sequence similarity
    findings: []
  - id: GO_REF:0000033
    title: Annotation inferences using phylogenetic trees
    findings: []
  - id: GO_REF:0000043
    title: Gene Ontology annotation based on UniProtKB/Swiss-Prot keyword mapping
    findings: []
  - id: GO_REF:0000107
    title: Automatic transfer of experimentally verified manual GO annotation data to orthologs using Ensembl Compara
    findings: []
  - id: GO_REF:0000120
    title: Combined Automated Annotation using Multiple IEA Methods
    findings: []
  - id: PMID:8597956
    title: Human eotaxin is a specific chemoattractant for eosinophil cells and provides a new mechanism to explain tissue eosinophilia.
    findings:
      - statement: Original cloning and functional characterization of human CCL11/eotaxin as a specific eosinophil chemoattractant.
  - id: PMID:8631813
    title: Molecular cloning of human eotaxin, an eosinophil-selective CC chemokine, and identification of a specific eosinophil eotaxin receptor, CC chemokine receptor 3.
    findings:
      - statement: Identified CCR3 as the specific receptor for eotaxin/CCL11.
  - id: PMID:9712872
    title: Solution structure of eotaxin, a chemokine that selectively recruits eosinophils in allergic inflammation.
    findings:
      - statement: Determined NMR solution structure of eotaxin showing typical chemokine fold.
      - statement: Showed monomer-dimer equilibrium under a wide range of conditions.
  - id: PMID:10072545
    title: Differential regulation of eosinophil chemokine signaling via CCR3 and non-CCR3 pathways.
    findings:
      - statement: Demonstrated eotaxin and eotaxin-2 are the most potent CCR3-acting chemokines for eosinophil shape change.
      - statement: Showed CCL11 induces cytoskeletal rearrangement and shape change in eosinophils via CCR3.
  - id: PMID:10201960
    title: Eotaxin activates T cells to chemotaxis and adhesion only if induced to express CCR3 by IL-2 together with IL-4.
    findings:
      - statement: Showed eotaxin can induce T cell chemotaxis and adhesion but only after IL-2/IL-4 induction of CCR3 expression.
  - id: PMID:10415069
    title: "Chemokine receptor expression and signaling in macaque and human fetal neurons and astrocytes: implications for the neuropathogenesis of AIDS."
    findings:
      - statement: Demonstrated CCR3 on fetal neurons responds to chemokine ligands with calcium mobilization.
  - id: PMID:10706854
    title: Eotaxin induces degranulation and chemotaxis of eosinophils through the activation of ERK2 and p38 mitogen-activated protein kinases.
    findings:
      - statement: Showed eotaxin induces concentration-dependent phosphorylation of ERK2 and p38 in eosinophils.
      - statement: Demonstrated MAP kinase activation is required for eotaxin-induced degranulation and chemotaxis.
  - id: PMID:10708591
    title: Cell-type-dependent induction of eotaxin and CCR3 by ionizing radiation.
    findings:
      - statement: Showed eotaxin expression is upregulated by ionizing radiation in dermal fibroblasts.
  - id: PMID:11425309
    title: NMR solution structure and backbone dynamics of the CC chemokine eotaxin-3.
    findings:
      - statement: Structural study of eotaxin-3 (CCL26), which shares CCR3 as receptor with CCL11.
  - id: PMID:18275857
    title: Stromal cell-derived factors 1alpha and 1beta, inflammatory protein-10 and interferon-inducible T cell chemo-attractant are novel substrates of dipeptidyl peptidase 8.
    findings:
      - statement: Surveyed chemokines for DPP8 cleavage; CCL11 was not a novel DPP8 substrate.
  - id: PMID:19525930
    title: CCR3 is a target for age-related macular degeneration diagnosis and therapy.
    findings:
      - statement: Demonstrated CCL11/eotaxins promote endothelial cell proliferation, actin polymerization, and migration via CCR3.
      - statement: Showed CCR3 targeting inhibits choroidal neovascularization.
      - statement: Genetic ablation of Ccl11 reduced CNV in mice.
  - id: PMID:20041150
    title: Missense mutations in the MEFV gene are associated with fibromyalgia syndrome and correlate with elevated IL-1beta plasma levels.
    findings:
      - statement: Measured CCL11 levels in plasma (demonstrates extracellular localization).
  - id: PMID:21314817
    title: "Neuropeptide Y, B-type natriuretic peptide, substance P and peptide YY are novel substrates of fibroblast activation protein-α."
    findings:
      - statement: FAP showed negligible hydrolysis of chemokines including CCL11.
  - id: PMID:23597562
    title: Inhibition of tumor angiogenesis and growth by a small-molecule multi-FGF receptor blocker with allosteric properties.
    findings:
      - statement: IntAct interaction data for CCL11-CCR3 binding derived from this study.
  - id: PMID:28381538
    title: Chemokine interactome mapping enables tailored intervention in acute and chronic inflammation.
    findings:
      - statement: Systematic mapping of chemokine-chemokine interactions including CCL11 heteromeric interactions.
  - id: PMID:33846499
    title: Eotaxin-1/CCL11 is involved in cell migration in rheumatoid arthritis.
    findings:
      - statement: Demonstrated CCL11 induces migration of RA FLS and THP-1 monocytes.
      - statement: Showed CCL11 siRNA knockdown reduces FLS migration.
      - statement: CCL11 levels elevated in RA serum and synovial fluid.
  - id: PMID:9558100
    title: Dendritic cells express multiple chemokine receptors used as coreceptors for HIV entry.
    findings:
      - statement: Described CCR3 as HIV coreceptor on dendritic cells.
  - id: Reactome:R-HSA-443986
    title: Receptor ACKR2 binds most inflammatory CC chemokines
    findings: []
  - id: Reactome:R-HSA-6793978
    title: Expression of STAT6-upregulated extracellular proteins
    findings: []