id: MODULE:efferocytosis_induced_macrophage_priming title: Efferocytosis-induced macrophage priming description: >- Engulfing an apoptotic cell changes how a macrophage responds to later challenges. In Drosophila embryos, each engulfed corpse triggers a brief rise in cytosolic calcium in the macrophage, which activates JNK. JNK signalling raises expression of the engulfment receptor Draper. Macrophages primed in this way migrate to wounds and take up bacteria; naive macrophages that have never met a corpse do neither. Beads of the same size are engulfed without causing the calcium rise or priming, so the trigger is the corpse itself. Priming is a switch rather than a dial: extra JNK or Draper does not make primed macrophages respond more strongly. status: DRAFT scope: ABSTRACT references: - id: PMID:27212238 title: Corpse Engulfment Generates a Molecular Memory that Primes the Macrophage Inflammatory Response. reference_review: relevance: HIGH correctness: VERIFIED review_notes: >- PubMed-verified; full text cached and read in full. Drosophila embryonic macrophages. Bead controls, calcium imaging and buffering, dominant-negative JNK and Draper overexpression define the programme. evidence: - source_id: PMID:27212238 title: Corpse Engulfment Generates a Molecular Memory that Primes the Macrophage Inflammatory Response. statement: The authors' model of the programme. supporting_text: Apoptotic corpse uptake triggers rapid intracellular calcium bursts in the macrophage, which, in turn, promotes JNK activity and increases Draper expression. - source_id: PMID:27212238 title: Corpse Engulfment Generates a Molecular Memory that Primes the Macrophage Inflammatory Response. statement: Engulfing beads does not prime, so the trigger is the corpse, not phagocytosis as such. supporting_text: Bead uptake did not, however, rescue the inflammatory wound recruitment defect of naive H99 macrophages - source_id: PMID:27212238 title: Corpse Engulfment Generates a Molecular Memory that Primes the Macrophage Inflammatory Response. statement: Priming is permissive; more JNK or Draper does not increase the response of already-primed cells. supporting_text: However, neither constitutive activation of JNK signaling nor Draper overexpression within wild-type macrophages affected wound recruitment (data not shown). notes: >- Boundary: this module starts after an apoptotic corpse has been engulfed and ends with a macrophage that can respond to wounds and microbes. Engulfment of the corpse belongs to MODULE:phagocytic_engulfment, where Draper also acts as an engulfment receptor. The outputs (migration to wounds, uptake of bacteria) are downstream processes, not parts of this module. GO has no term for this programme. The closest are GO:0042116 macrophage activation (used as the module concept) and GO:0090714 innate immunity memory response, which covers re-exposure to the same stimulus and so does not fit here. "efferocytosis-induced macrophage priming" (is_a GO:0042116, preceded_by GO:0043277) has been proposed to the GO editors in go-ontology#32748. Taxon scope: shown only in Drosophila. Draper belongs to the same receptor family as C. elegans CED-1, and JNK is conserved across animals, but whether corpse engulfment primes phagocytes this way in other animals is not known. In mammals, efferocytosis is usually anti-inflammatory (see MODULE:efferocytosis_induced_anti_inflammatory_programme). module: id: efferocytosis_induced_macrophage_priming label: Efferocytosis-induced macrophage priming module_type: SIGNALING_PATHWAY concepts: - preferred_term: macrophage activation term: id: GO:0042116 label: macrophage activation notes: >- Nearest existing term. A specific term, efferocytosis-induced macrophage priming, has been proposed to GO (go-ontology#32748). context: taxa: - preferred_term: Drosophila melanogaster term: id: NCBITaxon:7227 label: Drosophila melanogaster cell_types: - preferred_term: hemocyte (sensu Arthropoda) term: id: CL:0000387 label: hemocyte (sensu Arthropoda) notes: Embryonic macrophages (plasmatocytes). parts: - order: 1 role: corpse-triggered signalling node: id: corpse_triggered_jnk_signaling label: Corpse-triggered calcium and JNK signalling module_type: SIGNALING_PATHWAY description: >- Each corpse taken up is followed by a transient calcium rise in the macrophage. Calcium is needed for priming, and JNK acts downstream. The calcium channel or store involved has not been identified, so only the JNK step is modelled as an annoton. concepts: - preferred_term: JNK cascade term: id: GO:0007254 label: JNK cascade annotons: - id: bsk_jnk label: Basket (JNK) relays the corpse signal participant: selector_type: FAMILY family: preferred_term: JNK term: id: PANTHER:PTHR24055 label: MITOGEN-ACTIVATED PROTEIN KINASE representative_members: - preferred_term: MAPK8 (human) term: id: UniProtKB:P45983 label: Mitogen-activated protein kinase 8 - preferred_term: bsk (D. melanogaster) term: id: UniProtKB:P92208 label: Stress-activated protein kinase JNK ancestral_nodes: - preferred_term: PAINT node PTN001171982 term: id: PANTHER:PTN001171982 label: PTN001171982 description: >- Bilaterian PAINT IBD node (taxon:6072) in PTHR24055 propagating F:GO:0004705 JUN kinase activity and P:GO:0007254 JNK cascade, with bsk (FB:FBgn0000229) among the seeds. evidence: - source_id: GO_REF:0000033 statement: IBD propagation of JUN kinase activity from PAINT node PTN001171982 in PTHR24055. function: preferred_term: JUN kinase activity term: id: GO:0004705 label: JUN kinase activity processes: - preferred_term: JNK cascade term: id: GO:0007254 label: JNK cascade locations: - preferred_term: cytosol term: id: GO:0005829 label: cytosol role_description: >- Needed for priming but not for engulfment. Dominant-negative bsk blocks recruitment to wounds and uptake of bacteria and lowers Draper. JNK activity was read out with an AP-1 reporter. evidence: - source_id: PMID:27212238 title: Corpse Engulfment Generates a Molecular Memory that Primes the Macrophage Inflammatory Response. statement: JNK reporter activity needs corpses. supporting_text: H99 macrophages lacked TRE-eGFP reporter activity at all developmental stages (Figures 6D–6F), suggesting JNK signaling is activated downstream of corpse uptake. - source_id: PMID:27212238 title: Corpse Engulfment Generates a Molecular Memory that Primes the Macrophage Inflammatory Response. statement: Blocking JNK does not block engulfment. supporting_text: JNK inhibition did not affect macrophage numbers, developmental migration speeds, or corpse uptake (Figures S4A–S4C). - order: 2 role: receptor induction node: id: draper_induction label: Draper induction primes the macrophage module_type: REGULATORY_STEP description: >- JNK signalling raises draper transcript and protein, and Draper moves from the corpse-containing phagosome to the cell surface. Extra Draper alone primes naive macrophages and bypasses the need for JNK. annotons: - id: draper_receptor label: Draper receptor (induced) participant: selector_type: FAMILY family: preferred_term: CED-1/Draper engulfment receptor term: id: PANTHER:PTHR24035:SF109 label: PROTEIN DRAPER representative_members: - preferred_term: drpr (D. melanogaster) term: id: UniProtKB:Q9W0A0 label: Protein draper - preferred_term: ced-1 (C. elegans) term: id: UniProtKB:Q9XWD6 label: Cell death abnormality protein 1 notes: >- ced-1 is listed to show the subfamily is shared with nematodes, not to claim that ced-1 primes phagocytes. PANTHER's classification files place drpr and ced-1 in PTHR24035:SF109; UniProt's PANTHER cross-reference gives PTHR24043:SF8 instead. function: preferred_term: scavenger receptor activity term: id: GO:0005044 label: scavenger receptor activity locations: - preferred_term: plasma membrane term: id: GO:0005886 label: plasma membrane role_description: >- The output of priming. Raised Draper lets the macrophage sense wounds and bind and engulf bacteria. evidence: - source_id: PMID:27212238 title: Corpse Engulfment Generates a Molecular Memory that Primes the Macrophage Inflammatory Response. statement: Extra Draper primes naive macrophages without corpses. supporting_text: Elevated Draper expression therefore appears sufficient to prime macrophages for wound detection, bypassing the need for corpse uptake. - source_id: PMID:27212238 title: Corpse Engulfment Generates a Molecular Memory that Primes the Macrophage Inflammatory Response. statement: Draper acts downstream of JNK. supporting_text: Consistent with this, we find that overexpression of Draper can rescue the wound recruitment defect caused by macrophage JNK inhibition connections: - source: bsk_jnk target: draper_receptor connection_type: POSITIVELY_REGULATES description: JNK signalling raises draper expression; the transcription factor involved was not tested. knowledge_gaps: - gap_statement: >- The calcium channel or store that produces the corpse-triggered calcium rise, and how corpse uptake but not bead uptake opens it, are unknown. boundary: >- Calcium flashes accompany corpse uptake and buffering calcium blocks priming, but no channel, store or upstream receptor was identified. gap_kind: - BIOLOGY dark_aspect: BP_DARK status: OPEN significance: The first step of the programme has no gene product, so the module starts at JNK. resolution: >- Screen calcium channels and store-release machinery in macrophages for loss of corpse-associated calcium flashes and of priming. provenance: - reference_id: PMID:27212238 supporting_text: Notably, phagocytosis of fluorescent beads did not cause an observable increase in GCaMP3 fluorescence - gap_statement: >- Whether corpse engulfment primes phagocytes through JNK and a CED-1/Draper family receptor outside Drosophila is unknown. boundary: >- Shown only in Drosophila embryos. Mammalian efferocytosis is usually anti-inflammatory, and no mammalian counterpart of this priming has been described. gap_kind: - BIOLOGY dark_aspect: BP_DARK status: OPEN significance: Limits the taxonomic scope of the module. resolution: >- Test whether prior corpse engulfment changes the wound or infection response of zebrafish macrophages or C. elegans engulfing cells, and whether MEGF10 or ced-1 expression rises after engulfment. provenance: - reference_id: PMID:27212238 supporting_text: Apoptotic corpse uptake triggers rapid intracellular calcium bursts in the macrophage, which, in turn, promotes JNK activity and increases Draper expression.