Fig. 3: The mechanism of necroptosis leads to airflow limitation in COPD.

A Lung parenchymal epithelial cells undergo necroptosis due to direct exposure to toxic gases and particles (e.g. cigarette smoke). Excessive DAMPs are released and linked to PRRs on neighbouring macrophages after plasma membrane rupture, leading to pro-inflammatory cytokine production through multiple pathways and consequently causing inflammation and tissue remodelling in the lung parenchyma. In addition, the impaired ability of macrophages to phagocytose apoptotic epithelial cells in COPD and the slower clearance of necroptosis cells by macrophages can cause inadequate phagocytosis of dead cells, which triggers inflammation. B Epithelial cell membrane receptors bind to the corresponding ligands (e.g. TNF-α) and send signals to cause RIPK1 activation, followed by RIPK3 recruitment and phosphorylation. Mitochondrial ROS contributes to RIPK1 autophosphorylation, but the production is dependent on RIPK3. RIPK3 can also mediate MLKL phosphorylation, causing MLKL oligomerisation and translocation to the plasma membrane for forming plasma membrane pores and therefore releasing excessive DAMPs (including HMGB1 and ATP) to the extracellular environment. HMGB1 activates RAGE receptors on macrophages and promotes pro–IL-1β production via the MAPK/NF-κB pathway. Pro–IL-1β is cleaved by ATP-induced pathway products to form IL-1β. In addition, HMGB1 interacts with RAGE on the surface of macrophages and PS on the surface of apoptotic cells to participate in the inhibition of the macrophage uptake of apoptotic epithelial cells. ATP adenosine 5′-triphosphate, DAMPs damage-associated molecular patterns, HMGB1 high-mobility group box-1, IL interleukin, MAPK mitogen-activated protein kinase, MitoROS mitochondrial reactive oxygen species, MLKL mixed-lineage kinase domain-like, NF-κB nuclear factor kappa-B, P phosphorylates, PRRs pattern recognition receptors, PS phosphatidylserine, RAGE receptor for advanced glycation end-products, RIPK receptor-interacting protein kinase, TNF tumour necrosis factor.