MIF but not MIF-2 recruits inflammatory macrophages in an experimental polymicrobial sepsis model
Year: 2021
Type: article
Abstract: Excessive inflammation drives the progression from sepsis to septic shock. 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 8 hours after infectious insult. The recent description of a second MIF superfamily member, D-dopachrome tautomerase (D-DT/MIF-2), prompted closer investigation of MIF-dependent responses. 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 reduced numbers of small peritoneal macrophages (SPMs) that, in contrast to large peritoneal macrophages (LPMs), were recruited into the peritoneal cavity. LPMs produced higher quantities of MIF than SPMs, but SPMs expressed higher levels of inflammatory cytokines and the MIF receptors CD74 and CXCR2. Adoptive transfer of WT SPMs into Mif-/- hosts reduced the protective effect of Mif deficiency in polymicrobial sepsis. Notably, MIF-2 lacks the pseudo-(E)LR motif present in MIF that mediates CXCR2 engagement and SPM migration, supporting a specific role for MIF in the recruitment and accumulation of inflammatory SPMs.
DOI: 10.1172/jci127171
Authors: Pathricia Veronica Tilstam, Wibke Schulte, Thomas Holowka, Bong-Sung Kim, Jessica Nouws, Maor Sauler, Marta Piecychna, Georgios Pantouris, Elias Lolis, Lin Leng, Jürgen Bernhagen, Günter Fingerle-Rowson, Richard Bucala
Institutions: Harvard University, Yale University, Berlin Institute of Health at Charité - Universitätsmedizin Berlin, Charité – Universitätsmedizin Berlin, University Hospital Zurich, RWTH Aachen University, University of the Pacific, Munich Cluster for Systems Neurology, Institut für Schlaganfall- und Demenzforschung, Ludwig-Maximilians-Universität München, University of Cologne
Language: English
Subfield: Immunology
Field: Immunology and Microbiology
Domain: Life Sciences
Open Access status: bronze
Funders: Arthritis Foundation, Yale University, Deutsche Forschungsgemeinschaft, Charité – Universitätsmedizin Berlin, RWTH Aachen University, National Institutes of Health, National Heart, Lung, and Blood Institute, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Center for Advancing Translational Sciences
Awards: G1208489275, G1901460537, Aging and Innate Immune Mechanisms in Pulmonary Infection, G2313112155, Mechanisms of Rheumatoid Synovial Fibroblast Activation, G2523809757, G2699147485, G3537957661, MIF and DNA repair in the emphysematous lung, G4776778319, G4966563573, G6045158739, G670216319, G754071303, G804482151, Role of MIF and CD74 in the pathogenesis of emphysema, Defining the Pathogenic Contribution of High Genotypic MIF Expression, Yale Clinical and Translational Science Award, G914439352
OpenAlex ID: W3214831815