STAT6/Arg1 promotes microglia/macrophage efferocytosis and inflammation resolution in stroke mice

Cai, Wei; Dai, Xuejiao; Chen, Jie; Zhao, Jingyan; Xu, Mingyue; Zhang, Lili; Yang, Boyu; Zhang, Wenting; Rocha, Marcelo; Nakao, Toshimasa; Kofler, Julia; Shi, Yejie; Stetler, R. Anne; Hu, Xiaoming; Chen, Jun

doi:10.1172/jci.insight.131355

Cited by 151 publications

(130 citation statements)

References 41 publications

(54 reference statements)

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“…PPARγ was previously reported to promote phagocytic clearance of dead cells by macrophages in in vitro cultures, peripheral organs, and after intracerebral hemorrhage . Furthermore, a recent study from our group demonstrated a pivotal role of STAT6 in microglia/macrophage efferocytosis in the brain after ischemic stroke . In this study, we focused on molecules that are established regulators of phagocytosis.…”

Section: Discussionmentioning

confidence: 96%

“…[53][54][55] Furthermore, a recent study from our group demonstrated a pivotal role of STAT6 in microglia/macrophage efferocytosis in the brain after ischemic stroke. 56 In this study, we focused on molecules that are established regulators of phagocytosis. However, the prediction made by upstream regulator analysis may also uncover novel regulatory molecules.…”

Section: Discussionmentioning

confidence: 99%

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Macrophages reprogram after ischemic stroke and promote efferocytosis and inflammation resolution in the mouse brain

et al. 2019

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Aims Blood‐borne monocytes/macrophages infiltrate the brain in massive numbers after ischemic stroke, but their impact on poststroke brain injury and recovery remains elusive. This study examined the transcriptomic changes in monocytes/macrophages after ischemic stroke and the functional implications of these changes, particularly with regards to the contribution of these cells to the phagocytic clearance of dead/dying cells (efferocytosis) in the poststroke brain. Methods We performed whole‐genome RNA sequencing on the monocyte/macrophage population sorted from mouse brain and peripheral blood 5 days after permanent focal cerebral ischemia. In addition, the spatial and temporal profiles of macrophage efferocytosis were examined in vivo by immunohistochemistry 3‐7 days after brain ischemia. Results Robust transcriptomic changes occurred in monocytes/macrophages upon infiltrating the poststroke brain. Functional enrichment analysis revealed a transcriptome of brain macrophages that strongly favored efferocytic activity. A large number of efferocytosis‐related genes were upregulated in brain macrophages, the products of which are essential components involved in various steps of efferocytosis, such as chemotaxis, recognition of dead cells, engulfment, and processing of phagosomes. The efferocytic activity of brain macrophages were verified by immunohistochemistry, wherein Iba1‐labeled microglia/macrophages effectively cleared apoptotic neurons in the infarct during the subacute stage after brain ischemia. We also identified PPARγ and STAT6 as potential upstream regulators that shaped this proefferocytic and inflammation‐resolving transcriptome of macrophages in the poststroke brain. Conclusion Macrophages play a crucial role in the phagocytic clearance of dead neurons after ischemic stroke and promote the resolution of inflammation in the brain. Molecular therapies that enhance macrophage efferocytic capability may be promising treatments for ischemic stroke by facilitating inflammation resolution, brain repair, and recovery of neurological functions.

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Section: Discussionmentioning

confidence: 96%

Section: Discussionmentioning

confidence: 99%

Macrophages reprogram after ischemic stroke and promote efferocytosis and inflammation resolution in the mouse brain

et al. 2019

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“…Increasing evidence show that microglia polarize into a variety of phenotypes at different stages of injuries in CNS . Decreased expression of Arg1 in STAT6 −/− microglia/macrophages led to impairments in phagocytosis and loss of anti‐inflammatory modality which indicates that microglia phenotype is closely related to phagocytosis . Direct evidence for the relationship between specific microglia phenotype and phagocytosis should be investigated in the future.…”

Section: Discussionmentioning

confidence: 99%

P2Y6 receptor inhibition aggravates ischemic brain injury by reducing microglial phagocytosis

et al. 2020

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Introduction Clearance of damaged cells and debris is beneficial for the functional recovery after ischemic brain injury. However, the specific phagocytic receptor that mediates microglial phagocytosis after ischemic stroke is unknown. Aim To investigate whether P2Y6 receptor‐mediated microglial phagocytosis is beneficial for the debris clearance and functional recovery after ischemic stroke. Results The expression of the P2Y6 receptor in microglia increased within 3 days after transient middle cerebral artery occlusion. Inhibition of microglial phagocytosis by the selective inhibitor MRS2578 enlarged the brain atrophy and edema volume after ischemic stroke, subsequently aggravated neurological function as measured by modified neurological severity scores and Grid walking test. MRS2578 treatment had no effect on the expression of IL‐1α, IL‐1β, IL‐6, IL‐10, TNF‐α, TGF‐β, and MPO after ischemic stroke. Finally, we found that the expression of myosin light chain kinase decreased after microglial phagocytosis inhibition in the ischemic mouse brain, which suggested that myosin light chain kinase was involved in P2Y6 receptor‐mediated phagocytosis. Conclusion Our results indicate that P2Y6 receptor‐mediated microglial phagocytosis plays a beneficial role during the acute stage of ischemic stroke, which can be a therapeutic target for ischemic stroke.

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“…These results are some of the first (to our knowledge) to implicate lipin-1 activity in regulating continuing efferocytosis. IL-4 stimulation, as well as efferocytosis, leads to activation of transcription factors such as STAT6 and PPARs to drive expression of genes involved in fatty acid transport and b-oxidation (34,35). Lipin-1 binds to and augments PPAR activity in a variety of tissues (11,12).…”

Section: Discussionmentioning

confidence: 99%

Macrophage-Associated Lipin-1 Promotes β-Oxidation in Response to Proresolving Stimuli

et al. 2020

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Macrophages reprogram their metabolism to promote appropriate responses. Proresolving macrophages primarily use fatty acid oxidation as an energy source. Metabolites generated during the catabolism of fatty acids aid in the resolution of inflammation and tissue repair, but the regulatory mechanisms that control lipid metabolism in macrophages are not fully elucidated. Lipin-1, a phosphatidic acid phosphatase that has transcriptional coregulator activity, regulates lipid metabolism in a variety of cells. In this current study, we show that lipin-1 is required for increased oxidative phosphorylation in IL-4 stimulated mouse (Mus musculus) macrophages. We also show that the transcriptional coregulatory function of lipin-1 is required for b-oxidation in response to palmitate (free fatty acid) and apoptotic cell (human) stimulation. Mouse bone marrow-derived macrophages lacking lipin-1 have a reduction in critical TCA cycle metabolites following IL-4 stimulation, suggesting a break in the TCA cycle that is supportive of lipid synthesis rather than lipid catabolism. Together, our data demonstrate that lipin-1 regulates cellular metabolism in macrophages in response to proresolving stimuli and highlights the importance of aligning macrophage metabolism with macrophage phenotype.

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STAT6/Arg1 promotes microglia/macrophage efferocytosis and inflammation resolution in stroke mice

Cited by 151 publications

References 41 publications

Macrophages reprogram after ischemic stroke and promote efferocytosis and inflammation resolution in the mouse brain

Macrophages reprogram after ischemic stroke and promote efferocytosis and inflammation resolution in the mouse brain

P2Y6 receptor inhibition aggravates ischemic brain injury by reducing microglial phagocytosis

Macrophage-Associated Lipin-1 Promotes β-Oxidation in Response to Proresolving Stimuli

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