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 Article has an altmetric score of 4

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 7

Adoptive transfer of WT SPMs induces premature mortality in Mif–/– CLP mice.

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Adoptive transfer of WT SPMs induces premature mortality in Mif–/– CLP m...
(A) Hypothesis for the role of LPM-expressed MIF and CCL2 in the recruitment and retention of SPMs into peritonea followed by SPM cytokine production. (B) SPM migration into LPS-conditioned peritonea of WT mice measured 12 hours after the i.p. injection of 1 mg/kg recombinant MIF, MIF-2, or MIF lacking the pseudo-(E)LR motif (MIFR11A–D44A). Results are normalized against control group. Data from 3 independent experiments, n = 6 to 12 mice per group (1-way ANOVA with Tukey’s multiple-comparison test). (C) Directed migration in response to CCL2 of SPMs stimulated with recombinant MIF, MIF-2, MIFR11A–D44A, or MIF-2 with recombinant amino acid insertion of the pseudo-(E)LR motif (MIF-2A11R–G44D). Shown is the relative reduction in the CCL2-triggered chemotactic index. Data from 3 independent experiments, n = 12 samples per group (1-way ANOVA with Tukey’s multiple-comparison test). (D) Experimental scheme for the adoptive transfer of WT SPMs/LPMs and Mif–/– SPMs/LPMs into Mif–/– recipient mice. SPMs/LPMs were isolated by FACS from WT and Mif–/– donor mice, 0.75 × 106 SPMs/mouse and 0.5 × 105 LPMs/mouse transferred by i.p. injection into Mif–/– mice after CLP surgery. (E) Kaplan-Meier survival plots; (F) disease score; (G) surface body temperature of Mif–/– CLP mice after adoptive transfer of WT SPM (red), WT LPM (blue), vehicle control (green), Mif–/– SPM (dotted orange), and Mif–/– LPM (dotted magenta). Sham surgery control (black). n = 4 to 6 mice per group from 4 independent experiments. P values determined by log-rank (Mantel-Cox) test (E), Kruskal-Wallis test with Dunn’s multiple-comparison test (F), or 1-way ANOVA with Tukey’s multiple-comparison test (G). Significance for F and G was determined at 36 hours after injection. Images (A and D) created with Biorender.com. *P < 0.05; **P < 0.01; ***P < 0.001.