Macrophage migration inhibitory factor (MIF) as a regulator of barrier function and disease tolerance in the intestinal mucosa

Macrophage migration inhibitory factor (MIF) is a pro-inflammatory cytokine broadly expressed in the gastrointestinal tract. Previous data have shown that MIF-deficient (Mif ^−/−) mice harbor a unique gut microbiota characterized by high species diversity and enrichment in pathogens/pathobionts. Moreover, when this microbiota is transferred to Il10^−/− recipients, it induces lethal colitis. However, Mif ^−/− mice are able to tolerate their own microbiota without developing overt clinical signs of disease. To investigate how Mif ^−/− hosts harbor a pathogenic microbiota without exhibiting disease signs, we hypothesized that Mif^−/− mice display enhanced colonic mucosal barrier function.

To test this, colon samples from Mif ^−/− and wild‑type (WT) mice were analyzed under steady‑state conditions. No histological abnormalities or subclinical inflammation were observed, with similar Tnfa and Il6 levels. Mucus production was also comparable between genotypes. Notably, Mif ^−/− mice exhibited a higher frequency of EpCAM⁺ epithelial cells and a unique transcriptional profile, marked by upregulation of Il22, Il17a, Il33, and Tl1a, alongside downregulation of Il5, Il13, and Relmb — suggesting a homeostatic shift toward Th17‑type responses over Th2‑type responses.

Treatment with neutralizing anti‑IL‑22 antibodies did not induce disease, indicating that this cytokine may not be central to the mechanism. Together, the data show that Mif ^−/− mice maintain tissue integrity and absence of inflammation despite harboring a potentially pathogenic microbiota, revealing novel roles for MIF in intestinal homeostasis and microbiota selection.