Necroptosis Mediates Cigarette Smoke-Induced Inflammatory Responses in Macrophages

Introduction: 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.