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Type I interferons have immunomodulatory functions during infection with bacteria and viruses. They are vital for the host defense against viruses and extracellular bacteria. However, recent evidences show that IFN-I contributes to immunopathology during intracellular bacterial infection. We had previously shown that IFN-I receptor knock out mice (ifnar-/-) are less susceptible to S. Typhimurium infection and the macrophages are resistant to S. Typhimurium-induced cell death dependent on RIP kinases commonly known as necroptosis. We have now recently shown that IFN-I-signaling through the activation of RIP kinases and PGAM5 exacerbates necroptosis in Salmonella Typhimurium-infected macrophages by downregulating Nrf2-dependent cytoprotective response mechanisms [Hos et al, JCB 2017].