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STAT6 induces expression of Gas6 in macrophages to clear apoptotic neutrophils and resolve inflammation.

ABSTRACT: Efferocytosis of apoptotic neutrophils (PMNs) by alveolar macrophages (AMФs) is vital for resolution of inflammation and tissue injury. Here, we investigated the role of AMФ polarization and expression of the efferocytic ligand Gas6 in restoring homeostasis. In the murine model of lipopolysaccharide (LPS)-induced acute lung injury (ALI), we observed augmented temporal generation of cytokines IL-4 and TSG6 in bronchoalveolar fluid (BALF). Interestingly, we also observed increased expression of antiinflammatory markers consistent with a phenotype shift in AMФs. In particular, AMФs expressed the efferocytic ligand Gas6. In vitro priming of bone marrow-derived macrophages (BMMФs) with IL-4 or TSG6 also induced MФ transition and expression of Gas6. TSG6- or IL-4-primed BMMФs induced efferocytosis of apoptotic PMNs compared with control BMMФs. Adoptive transfer of TSG6- or IL-4-primed BMMФs i.t. into LPS-challenged mice more rapidly and effectively cleared PMNs in lungs compared with control BMMФs. We demonstrated that expression of Gas6 during AMФ transition was due to activation of the transcription factor signal transducer and activator of transcription-6 (STAT6) downstream of IL-4 or TSG6 signaling. Adoptive transfer of Gas6-depleted BMMФs failed to clear PMNs in lungs following LPS challenge and mice showed severely defective resolution of lung injury. Thus, activation of STAT6-mediated Gas6 expression during macrophage phenotype transition resulting in efferocytosis of PMNs plays a crucial role in the resolution of inflammatory lung injury.

SUBMITTER: Nepal S

PROVIDER: S-EPMC6697797 | biostudies-other | 2019 Aug

REPOSITORIES: biostudies-other

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STAT6 induces expression of Gas6 in macrophages to clear apoptotic neutrophils and resolve inflammation.

Nepal Saroj S Tiruppathi Chinnaswamy C Tsukasaki Yoshikazu Y Farahany Joseph J Mittal Manish M Rehman Jalees J Prockop Darwin J DJ Malik Asrar B AB

Proceedings of the National Academy of Sciences of the United States of America 20190730 33

Efferocytosis of apoptotic neutrophils (PMNs) by alveolar macrophages (AMФs) is vital for resolution of inflammation and tissue injury. Here, we investigated the role of AMФ polarization and expression of the efferocytic ligand Gas6 in restoring homeostasis. In the murine model of lipopolysaccharide (LPS)-induced acute lung injury (ALI), we observed augmented temporal generation of cytokines IL-4 and TSG6 in bronchoalveolar fluid (BALF). Interestingly, we also observed increased expression of an ...[more]

PMID: 31363052

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Project description:Alpha 1 antitrypsin deficiency (AATD) is an autosomal co-dominant disorder characterized by a low level of circulating AAT, which significantly reduces protection for the lower airways against proteolytic burden caused by neutrophils. Neutrophils, which are terminally differentiated innate immune cells and play a critical role to clear pathogens, accumulate excessively in the lung of AATD individuals. The neutrophil burden in AATD individuals increases the risk for early-onset destructive lung diseases by producing neutrophil products such as reactive oxygen radicals and various proteases. The level of AAT in AATD individuals is not sufficient to inhibit the activity of neutrophil chemotactic factors such as CXCL-8 and LTB4, which could lead to alveolar neutrophil accumulation in AATD individuals. However, as neutrophils have a short lifespan, and apoptotic neutrophils are rapidly cleared by alveolar macrophages that outnumber the apoptotic neutrophils in the pulmonary alveolus, the increased chemotaxis activity does not fully explain the persistent neutrophil accumulation and the resulting chronic inflammation in AATD individuals. Here, we propose that the ability of alveolar macrophages to clear apoptotic neutrophils is impaired in AATD individuals and it could be the main driver to cause neutrophil accumulation in their lung. This study demonstrates that Z-AAT variant significantly increases the expression of pro-inflammatory cytokines including CXCL-8, CXCL1, LTB4, and TNFα in LPS-treated macrophages. These cytokines play a central role in neutrophil recruitment to the lung and in clearance of apoptotic neutrophils by macrophages. Our result shows that LPS treatment significantly reduces the efferocytosis ability of macrophages with the Z-AAT allele by inducing TNFα expression. We incubated monocyte-derived macrophages (MDMs) with apoptotic neutrophils and found that after 3 h of co-incubation, the expression level of CXCL-8 is reduced in M-MDMs but increased in Z-MDMs. This result shows that the expression of inflammatory cytokines could be increased by impaired efferocytosis. It indicates that the efferocytosis ability of macrophages plays an important role in regulating cytokine expression and resolving inflammation. Findings from this study would help us better understand the multifaceted effect of AAT on regulating neutrophil balance in the lung and the underlying mechanisms.

Project description:INTRODUCTION: Inflammation of the synovial membrane plays an important role in the pathophysiology of osteoarthritis (OA). The synovial tissue of patients with initial OA is characterized by infiltration of mononuclear cells and production of proinflammatory cytokines and other mediators of joint injury. The objective was to evaluate the effect of low-level laser therapy (LLLT) operating at 50 mW and 100 mW on joint inflammation in rats induced by papain, through histopathological analysis, differential counts of inflammatory cells (macrophages and neutrophils), as well as gene expression of interleukin 1-beta and 6 (IL-1? and IL-6), and protein expression of tumor necrosis factor alpha (TNF?). METHODS: Male Wistar rats (n = 60) were randomly divided into four groups of 15 animals, namely: a negative control group; an inflammation injury positive control group; a 50 mW LLLT group, subjected to injury and treated with 50 mW LLLT; and a 100 mW LLLT group, subjected to injury and treated with 100 mW LLLT. The animals were subject to joint inflammation (papain solution, 4%) and then treated with LLLT (808 nm, 4 J, 142.4 J/cm(2), spot size 0.028 for both groups). On the day of euthanasia, articular lavage was collected and immediately centrifuged; the supernatant was saved for analysis of expression of TNF? protein by enzyme-linked immunosorbent assay and expression of IL-1? and IL-6 mRNA by real-time polymerase chain reaction. A histologic examination of joint tissue was also performed. For the statistical analysis, analysis of variance with Tukey's post-hoc test was used for comparisons between each group. All data are expressed as mean values and standard deviation, with P < 0.05. RESULTS: Laser treatment with 50 mW was more efficient than 100 mW in reducing cellular inflammation, and decreased the expression of IL-1? and IL-6. However, the 100 mW treatment led to a higher reduction of TNF? compared with the 50 mW treatment. CONCLUSIONS: LLLT with 50 mW was more efficient in modulating inflammatory mediators (IL-1?, IL-6) and inflammatory cells (macrophages and neutrophils), which correlated with the histology that showed a reduction in the inflammatory process.

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STAT6 induces expression of Gas6 in macrophages to clear apoptotic neutrophils and resolve inflammation.

Publications

STAT6 induces expression of Gas6 in macrophages to clear apoptotic neutrophils and resolve inflammation.

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