Lack of STAT6 enhances murine acute lung injury through NLRP3/p38 MAPK signaling pathway in macrophages

Abstract

Background Signal transducer and activator of transcription 6 (STAT6) is an intracelluar transcriotion factor and NLRP3 (Nod-like receptor containing a pyrin domain 3) is a component of NLRP3 inflammasome in pyroptotic cells. There was increased activation of STAT6 and expression of NLRP3 in mice with murine acute lung injury (ALI). However, it is unknown their roles in the development of murine ALI. We in this study, investigated the effects of STAT6 signaling on murine ALI and pyroptosis in STAT6 knock-out (KO) mice and macrophages. Results STAT6 was activated in the lung tissues of mice 2 days after intratracheal treatmemt with 5 mg/kg LPS. Lack of STAT6 expression in KO mice induced more severe lung inflammation, associated with elevated neutrophil influx and expression of TNF-alpha, IL-6 and IL-1beta in the inflamed lung tissues. In addition, the expression of NLRP3, ASC (apoptosis-associated speck-like protein containing a CARD), p-p38 MAPK (p38 mitogen-activated protein kinase) and ratio of LC3-II/I (microtubule-associated protein-1 light chain-3) was increased, accompanied with the increased polarization of Siglec-F(−) subtype macrophages in KO mice with ALI. Further studies in bone marrow-derived macrophages (BMDMs) revealed that lack of STAT6 increased the expression of NLRP3 and p-p38 MAPK, in association with elevated expression of TNF-alpha, IL-1beta and Calreticulin in LPS-treated KO BMDMs. Conclusions Lack of STAT6 exacerbated murine ALI through improving the expression of NLRP3 and activation of p38 MAPK in macrophages. STAT6 has an immune suppressive role in the development of ALI and would be a promising therapeutic target in the treatment of ALI and possibly among patients with acute respiratory distress syndrome (ARDS).

Daucosterol Alleviates Alcohol−Induced Hepatic Injury and Inflammation through P38/NF−κB/NLRP3 Inflammasome Pathway

“…The p38 MAPK is an important member of MAPKs, which not only involves the cell cycle, cell death, development, differentiation, senescence, and tumorigenesis but also regulates inflammation as a specific serine/threonine kinase [ 35 ]. Research has shown that inhibition of p38 plays a protective role in many inflammatory disease models, including Parkinson’s disease, acute lung injury, colitis, and diabetic nephropathy, by regulating the activation of NLRP3 inflammasome [ 54 , 55 , 56 , 57 ]. In our study, p38 was phosphorylated by alcohol and inhibited by DAU in the ALD mice model.…”

Immunotherapy strategies and prospects for acute lung injury: Focus on immune cells and cytokines

“…The role of NLRP3 in ALI has been controversial. Studies have shown that macrophages are over-activated in LPS-induced ALI, activating NLRP3 inflammasome and triggering pyroptosis, a process that exacerbates the disease of ALI ( Li et al, 2018 ; Hu et al, 2022 ). In addition, NLRP3-mediated pyroptosis may not be limited to macrophages, but may also be discovered in neutrophils ( Feng et al, 2017 ).…”