Necrotic cell death increases the release of macrophage migration inhibitory factor by monocytes/macrophages

Macrophage migration inhibitory factor (MIF) is a pleiotropic inflammatory molecule with both cytokine and noncytokine activity. MIF is constitutively released from multiple cell types via an unconventional secretory pathway that is not well defined. Here, we looked at MIF release from human and mouse monocytes/macrophages in response to different stimuli. While MIF release was not significantly altered in response to lipopolysaccharide or heat‐killed Escherichia coli, cytotoxic stimuli strongly promoted release of MIF. MIF release was highly upregulated in cells undergoing necrosis, necroptosis and NLRP3 inflammasome‐dependent pyroptosis. Our data suggest that cell death represents a major route for MIF release from myeloid cells. The functional significance of these findings and their potential importance in the context of autoimmune and inflammatory diseases warrant further investigation. We have shown that macrophage migration inhibitory factor (MIF) is released by monocytes/macrophages when they die, by necrosis, necroptosis and pyroptosis. This could have implications for MIF in autoimmune and inflammatory diseases, in which cell death or defective clearance of apoptotic cells (or both) are critical triggers of pathology. See also: News and Commentary byHoffmann & Bernhagen