Efferocytosis-induced macrophage priming

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.

MODULE:efferocytosis_induced_macrophage_primingDRAFTABSTRACTSignaling Pathwaymodules/efferocytosis_induced_macrophage_priming.yaml
macrophage activationGO:0042116
PMID:27212238
Corpse Engulfment Generates a Molecular Memory that Primes the Macrophage Inflammatory Response.
The authors' model of the programme.
Apoptotic corpse uptake triggers rapid intracellular calcium bursts in the macrophage, which, in turn, promotes JNK activity and increases Draper expression.
PMID:27212238
Corpse Engulfment Generates a Molecular Memory that Primes the Macrophage Inflammatory Response.
Engulfing beads does not prime, so the trigger is the corpse, not phagocytosis as such.
Bead uptake did not, however, rescue the inflammatory wound recruitment defect of naive H99 macrophages
PMID:27212238
Corpse Engulfment Generates a Molecular Memory that Primes the Macrophage Inflammatory Response.
Priming is permissive; more JNK or Draper does not increase the response of already-primed cells.
However, neither constitutive activation of JNK signaling nor Draper overexpression within wild-type macrophages affected wound recruitment (data not shown).

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).

3Nodes
2Parts
0Variant Sets
0Variants
2Annotons
1Connections

Derived QC

Recommended-field compliance

78.6% recommended fields populated
  • references[0] · findings (0/1)
  • knowledge_gaps[0].provenance[0] · reference_section_type (0/1)
  • knowledge_gaps[1].provenance[0] · reference_section_type (0/1)

Module deep research

✗ none found

No MODULE:efferocytosis_induced_macrophage_priming deep-research report alongside the module YAML.

Leaf nodes lacking representative members

✓ representative grounding skipped for abstract module.

Template conformance

✓ every declared conforms_to bundle matches its template motif.

Function consistency and core coverage

3 gene-function check(s) reflected in core functions · 0 conflict(s) · 3 evidence or coverage gap(s) (6 comparison(s))

Retained noncore functions are reported separately; they do not require promotion to core functions. Support from representative genes does not establish conservation across the whole family. Missing reviews or identifiers leave a claim unverified.

AnnotonParticipantFunctionAssessment
bsk_jnk MAPK8 (human)
UniProtKB:P45983
Family Representative 		JUN kinase activity
GO:0004705 		Core Supported
The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
bsk_jnk bsk (D. melanogaster)
UniProtKB:P92208
Family Representative 		JUN kinase activity
GO:0004705 		Review Missing
No ai-review exists for this protein; its function and core-function coverage cannot yet be checked.
draper_receptor drpr (D. melanogaster)
UniProtKB:Q9W0A0
Family Representative 		scavenger receptor activity
GO:0005044 		Core Supported
The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
draper_receptor ced-1 (C. elegans)
UniProtKB:Q9XWD6
Family Representative 		scavenger receptor activity
GO:0005044 		Core Supported
The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
bsk_jnk JNK
PANTHER:PTHR24055
Family 		JUN kinase activity
GO:0004705 		Family Function Unreviewed
Family review leaves GO:0004707 UNRESOLVED. The cucumber target has a MAP-kinase conserved-site signature, supporting MAPK-type phosphotransfer rather than an arbitrary kinase label. Classical MAPKs and divergent CMGC relatives nevertheless differ in activation-loop regulation and upstream kinases. The complete functional boundary cannot be inferred from a rule-generated catalytic equation or extended to every CMGC-like member without catalytic and activation-mechanism evidence.
draper_receptor CED-1/Draper engulfment receptor
PANTHER:PTHR24035:SF109
Family 		scavenger receptor activity
GO:0005044 		Family Review Missing
No supported structured family review is available for PANTHER:PTHR24035:SF109.

Gene-review completeness (3/4 grounded genes reviewed)

1 complete review(s) · 3 with deep research · 1 missing review · 0 reviewed but lacking deep research

Gene Review Complete Deep research
ced-1 Q9XWD6 ✓ ✓ ✓
drpr Q9W0A0 ✓ 49/51 ✓
MAPK8 P45983 ✓ 150/152 ✓
bsk (D. melanogaster) P92208 ✗ — —

Details

Context
Drosophila melanogasterNCBITaxon:7227
hemocyte (sensu Arthropoda)CL:0000387
Efferocytosis-induced macrophage primingSignaling Pathwayefferocytosis_induced_macrophage_priming
macrophage activationGO:0042116
Context
Drosophila melanogasterNCBITaxon:7227
hemocyte (sensu Arthropoda)CL:0000387

Connections

bsk_jnk -> draper_receptor Positively Regulates
JNK signalling raises draper expression; the transcription factor involved was not tested.
Part 1: corpse-triggered signalling
Corpse-triggered calcium and JNK signallingSignaling Pathwaycorpse_triggered_jnk_signaling

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.

JNK cascadeGO:0007254

Annotons

Basket (JNK) relays the corpse signal
bsk_jnk
Participant: Family: JNK
Family:
JNKPANTHER:PTHR24055
Representative Members: MAPK8 (human)UniProtKB:P45983 bsk (D. melanogaster)UniProtKB:P92208

Function

JUN kinase activityGO:0004705

Processes

JNK cascadeGO:0007254

Locations

cytosolGO:0005829

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.

PMID:27212238
Corpse Engulfment Generates a Molecular Memory that Primes the Macrophage Inflammatory Response.
JNK reporter activity needs corpses.
H99 macrophages lacked TRE-eGFP reporter activity at all developmental stages (Figures 6D–6F), suggesting JNK signaling is activated downstream of corpse uptake.
PMID:27212238
Corpse Engulfment Generates a Molecular Memory that Primes the Macrophage Inflammatory Response.
Blocking JNK does not block engulfment.
JNK inhibition did not affect macrophage numbers, developmental migration speeds, or corpse uptake (Figures S4A–S4C).
Part 2: receptor induction
Draper induction primes the macrophageRegulatory Stepdraper_induction

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

Draper receptor (induced)
draper_receptor
Participant: Family: CED-1/Draper engulfment receptor
Family:
CED-1/Draper engulfment receptorPANTHER:PTHR24035:SF109
Representative Members: drpr (D. melanogaster)UniProtKB:Q9W0A0 ced-1 (C. elegans)UniProtKB:Q9XWD6

Function

scavenger receptor activityGO:0005044

Locations

plasma membraneGO:0005886

The output of priming. Raised Draper lets the macrophage sense wounds and bind and engulf bacteria.

PMID:27212238
Corpse Engulfment Generates a Molecular Memory that Primes the Macrophage Inflammatory Response.
Extra Draper primes naive macrophages without corpses.
Elevated Draper expression therefore appears sufficient to prime macrophages for wound detection, bypassing the need for corpse uptake.
PMID:27212238
Corpse Engulfment Generates a Molecular Memory that Primes the Macrophage Inflammatory Response.
Draper acts downstream of JNK.
Consistent with this, we find that overexpression of Draper can rescue the wound recruitment defect caused by macrophage JNK inhibition