Necroptosis Mediates Cigarette Smoke-Induced Inflammatory Responses in Macrophages

Abstract

Yong Wang, Xiao-Ke Wang, Pei-Pei Wu, Yi Wang, Liang-Yu Ren, Ai-Hui Xu Department of Respiratory and Critical Care Medicine, First Affiliated Hospital of Anhui Medical University, Hefei 230022, People’s Republic of ChinaCorrespondence: Ai-Hui XuDepartment of Respiratory and Critical Care Medicine, First Affiliated Hospital of Anhui Medical University, 218 Jixi Road, Hefei 230022, People’s Republic of ChinaEmail [email protected]: Cigarette smoke (CS)-induced inflammation in macrophages is involved in the pathological process of chronic obstructive pulmonary disease (COPD). Necroptosis, which is a form of programmed necrosis, has a close relationship with robust inflammation, while its roles in COPD are unclear.Materials and Methods: Necroptosis markers were measured in mouse alveolar macrophages and cultured bone marrow-derived macrophages (BMDMs). Necroptosis inhibitors were used to block necroptosis in BMDMs, and inflammatory cytokines were detected. We further explored the related signaling pathways.Results: In this study, we demonstrated the way in which necroptosis, in addition to its upstream and downstream signals, regulates CS-induced inflammatory responses in macrophages. We observed that CS exposure caused a significant increase in the levels of necroptosis markers (receptor interacting kinases [RIPK] 1 and 3) in mouse alveolar macrophages and BMDMs. Pharmacological inhibition of RIPK1 or 3 caused a significant suppression in CS extract (CSE)-induced inflammatory cytokines, chemokine ligands (CXCL) 1 and 2, and interleukin (IL)-6 in BMDMs. CSE-induced necroptosis was regulated by mitochondrial reactive oxygen species (mitoROS), which also promoted inflammation in BMDMs. Furthermore, necroptosis regulated CSE-induced inflammatory responses in BMDMs, most likely through activation of the nuclear factor-κB pathway.Conclusion: Taken together, our results demonstrate that mitoROS-dependent necroptosis is essential for CS-induced inflammation in BMDMs and suggest that inhibition of necroptosis in macrophages may represent effective therapeutic approaches for COPD patients.Keywords: cigarette smoke, macrophage, necroptosis, inflammatory response, NF-κB pathway

Keywords

• cigarette smoke
• macrophage
• necroptosis
• inflammatory response
• nf-κb pathway