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The electron transport chain (ETC) couples oxidative phosphorylation (OXPHOS) with ATP synthase to drive the generation of ATP. In immune cells, research surrounding the ETC has drifted away from bioenergetics since the discovery of cytochrome c (Cyt c) release as a signal for programmed cell death. Complex I has been shown to generate reactive oxygen species (ROS), with key roles identified in inflammatory macrophages and T helper 17 cells (TH17) cells. Complex II is the site of reverse electron transport (RET) in inflammatory macrophages and is also responsible for regulating fumarate levels linking to epigenetic changes. Complex III also produces ROS which activate hypoxia‐inducible factor 1‐alpha (HIF‐1α) and can participate in regulatory T cell (Treg) function. Complex IV is required for T cell activation and differentiation and the proper development of Treg subsets. Complex V is required for TH17 differentiation and can be expressed on the surface of tumor cells where it is recognized by anti‐tumor T and NK cells. In this review, we summarize these findings and speculate on the therapeutic potential of targeting the ETC as an anti‐inflammatory strategy.

Severe coronavirus disease 2019 (COVID-19) is characterized by respiratory failure, shock, or multiorgan dysfunction, often accompanied by systemic hyperinflammation and dysregulated cytokine release. These features are linked to the intense and rapid stimulation of the innate immune response. The NLRP3 inflammasome is a central player in inflammatory macrophage activation which via caspase-1 activation leads to the release of the mature forms of the pro-inflammatory cytokines IL-1β and IL-18, and via cleavage of Gasdermin D pyroptosis, an inflammatory form of cell death. Here we discuss the role of NLRP3 activation in COVID-19 and clinical trials currently underway to target NLRP3 to treat severe COVID-19.