STAT6/Arg1 promotes microglia/macrophage efferocytosis and inflammation resolution in stroke mice.
JCI Insight
; 4(20)2019 10 17.
Article
in En
| MEDLINE
| ID: mdl-31619589
ABSTRACT
Efferocytosis, or phagocytic clearance of dead/dying cells by brain-resident microglia and/or infiltrating macrophages, is instrumental for inflammation resolution and restoration of brain homeostasis after stroke. Here, we identify the signal transducer and activator of transcription 6/arginase1 (STAT6/Arg1) signaling axis as a potentially novel mechanism that orchestrates microglia/macrophage responses in the ischemic brain. Activation of STAT6 was observed in microglia/macrophages in the ischemic territory in a mouse model of stroke and in stroke patients. STAT6 deficiency resulted in reduced clearance of dead/dying neurons, increased inflammatory gene signature in microglia/macrophages, and enlarged infarct volume early after experimental stroke. All of these pathological changes culminated in an increased brain tissue loss and exacerbated long-term functional deficits. Combined in vivo analyses using BM chimeras and in vitro experiments using microglia/macrophage-neuron cocultures confirmed that STAT6 activation in both microglia and macrophages was essential for neuroprotection. Adoptive transfer of WT macrophages into STAT6-KO mice reduced accumulation of dead neurons in the ischemic territory and ameliorated brain infarction. Furthermore, decreased expression of Arg1 in STAT6-/- microglia/macrophages was responsible for impairments in efferocytosis and loss of antiinflammatory modality. Our study suggests that efferocytosis via STAT6/Arg1 modulates microglia/macrophage phenotype, accelerates inflammation resolution, and improves stroke outcomes.
Key words
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Arginase
/
Microglia
/
Brain Infarction
/
STAT6 Transcription Factor
/
Macrophages
Type of study:
Prognostic_studies
Limits:
Aged80
/
Animals
/
Female
/
Humans
/
Male
Language:
En
Journal:
JCI Insight
Year:
2019
Document type:
Article
Affiliation country:
United States