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Updated: Oct 11, 2025
Colon Ascendens Stent Peritonitis CASP - a Standardized Model for Polymicrobial Abdominal Sepsis
Published on: December 18, 2010
MIF but not MIF-2 recruits inflammatory macrophages in an experimental polymicrobial sepsis model
Pathricia Veronica Tilstam1,2, Wibke Schulte1,3,4,5, Thomas Holowka1
1Department of Internal Medicine, Yale University School of Medicine, New Haven, Connecticut, USA.
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.
Insights
Macrophage migration inhibitory factor (MIF) deficiency improves survival in sepsis by reducing inflammatory small peritoneal macrophage (SPM) recruitment. MIF, not MIF-2, drives SPM accumulation via CXCR2, highlighting MIF
Area of Science:
- Immunology
- Molecular Biology
- Pathophysiology
Background:
- Sepsis progression to septic shock is driven by excessive inflammation.
- Macrophage migration inhibitory factor (MIF) and its homolog MIF-2 are implicated in inflammatory responses.
- MIF polymorphisms correlate with infection mortality, and anti-MIF therapy shows promise in experimental models.
Purpose of the Study:
- To investigate the specific roles of MIF and MIF-2 in polymicrobial sepsis.
- To determine the contribution of macrophage populations, particularly small peritoneal macrophages (SPMs), to sepsis pathogenesis.
- To elucidate the mechanisms of MIF-mediated macrophage recruitment and accumulation.
Main Methods:
- Utilized Mif-/- and Mif-2-/- mice subjected to polymicrobial sepsis.
- Analyzed peritoneal macrophage populations (SPMs and LPMs) for recruitment, cytokine expression, and receptor levels.
- Performed adoptive transfer experiments using wild-type SPMs in Mif-/- hosts.
Main Results:
- Mif deficiency, but not Mif-2 deficiency, conferred a survival benefit in polymicrobial sepsis.
- Survival was linked to reduced recruitment of SPMs, which express higher levels of inflammatory cytokines and MIF receptors (CD74, CXCR2).
- Adoptive transfer of WT SPMs negated the protective effect of Mif deficiency, confirming SPM involvement.
Conclusions:
- MIF plays a critical role in the recruitment and accumulation of inflammatory SPMs during sepsis.
- MIF-2 does not appear to mediate SPM migration, lacking a key motif for CXCR2 engagement.
- Targeting MIF-mediated SPM recruitment represents a potential therapeutic strategy for sepsis.
