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Significance Sepsis is a multifactorial syndrome with increasing incidence and significant mortality. While previous work implicated tumor necrosis factor (TNF)-induced cell death in sepsis, a role for interferon-gamma (IFNγ), which synergizes with TNF to activate macrophages, is incompletely understood. We demonstrate using genome-wide CRISPR/Cas9 screening that genes regulating the cytosolic degradative pathway of autophagy protect against IFNγ-induced cell death. This cell death requires TNF and its receptor and depends on the downstream cell death mediators caspase-8 and RIPK1. Moreover, mice with myeloid cell autophagy gene deficiency are hypersusceptible to fatal TNF-induced shock, which also depends on IFNγ signaling and RIPK1. These findings identify autophagy genes as important regulators of IFNγ- and TNF-mediated cell death with implications for fatal systemic inflammatory responses.

Autophagy genes in myeloid cells counteract IFNγ-induced TNF-mediated cell death and fatal TNF-induced shock