MIF but not MIF-2 recruits inflammatory macrophages in an experimental polymicrobial sepsis model
Pathricia Veronica Tilstam, … , Günter Fingerle-Rowson, Richard Bucala
Pathricia Veronica Tilstam, … , Günter Fingerle-Rowson, Richard Bucala
Published December 1, 2021
Citation Information: J Clin Invest. 2021;131(23):e127171. https://doi.org/10.1172/JCI127171.
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Research Article Immunology Inflammation

MIF but not MIF-2 recruits inflammatory macrophages in an experimental polymicrobial sepsis model

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.

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

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Figure 3

Macrophages are the predominant cell type in CLP and can be classified into SPM and LPM subpopulations.

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Macrophages are the predominant cell type in CLP and can be classified i...
(A) Peritoneal cells were stained for flow cytometry and relative numbers of CD11b+F4/80+ macrophages, CD115–Gr1hi neutrophils, CD115+Gr1hi monocytes, Siglec F+ eosinophils, CD11c+ DCs, and CD3+/CD19+ lymphocytes; (A) was determined as percentage of CD45+ cells and (B) measured as absolute cell number. Plot of n = 7 mice from 2 separate experiments. Two-way ANOVA with Sidak’s multiple-comparison test. (C) Representative gating strategy for the identification of small (SPM) and large (LPM) peritoneal macrophages in the peritoneal lavage of WT mice 22 hours after CLP or sham surgery. (D) Cytospins of SPMs and LPMs isolated from peritoneal lavage of septic mice and stained with Wright-Giemsa stain. Macrophage size was determined by ImageJ software from n = 11 animals. SPMs measured 10.9 ± 0.3 μm; the size of LPMs was 15.6 ± 0.5 μm (unpaired, 2-tailed Student’s t test). *P < 0.05; **P < 0.01.