Selective Recruitment of Lethal Pro-inflammatory Macrophages in Sepsis by MIF but not D-DT (MIF-2)

Abstract Sepsis is a leading cause of mortality with an estimated global incidence of 30 million cases annually. Current paradigms emphasize the role of an overwhelming or dysregulated inflammatory response in sepsis lethality, but to date interventions aimed at particular inflammatory pathways have been unsuccessful. Macrophage migration inhibitory factor (MIF) is of interest because MIF promoter polymorphisms predict mortality in different infections and anti-MIF antibody improves survival in experimental models when administered eight hours after infectious insult. The recent description of a second MIF superfamily member, D-dopachrome tautomerase (D-DT/MIF-2), prompts closer investigation of MIF-dependent responses. This study provides new insight into the pathophysiology of polymicrobial sepsis by revealing a direct role for MIF, but not its close structural homolog D-DT/MIF-2, in activating and recruiting a lethal macrophage subset. We subjected Mif −/− and Mif-2−/− mice to polymicrobial sepsis and observed a survival benefit with Mif but not Mif-2 deficiency. Survival was associated with lower levels of small peritoneal macrophages (SPMs) that, in contrast to large peritoneal macrophages (LPMs), are recruited to site of peritoneal inflammation during sepsis. LPMs produce higher quantities of MIF than SPMs, but SPMs express higher levels of inflammatory cytokines and MIF receptors CD74 and CXCR2. Adoptive transfer of SPMs into Mif −/− hosts abrogated the protective effect of Mif deficiency. Notably, MIF-2 lacks the pseudo-(E)LR motif present in MIF that mediates CXCR2 engagement and SPM migration, supporting MIF’s selective role in the recruitment and accumulation of lethal inflammatory SPMs.