Differential regulation of macrophage activation by the MIF cytokine superfamily members MIF and MIF‐2 in adipose tissue during endotoxemia

Abstract

Sepsis is a leading cause of death worldwide and recent studies have shown white adipose tissue (WAT) to be an important regulator in septic conditions. In the present study, the role of the inflammatory cytokine macrophage migration inhibitory factor (MIF) and its structural homolog D‐dopachrome tautomerase (D‐DT/MIF‐2) were investigated in WAT in a murine endotoxemia model. Both MIF and MIF‐2 levels were increased in the peritoneal fluid of LPS‐challenged wild‐type mice, yet, in visceral WAT, the proteins were differentially regulated, with elevated MIF but downregulated MIF‐2 expression in adipocytes. Mif gene deletion polarized adipose tissue macrophages (ATM) toward an anti‐inflammatory phenotype while Mif‐2 gene knockout drove ATMs toward a pro‐inflammatory phenotype and Mif‐deficiency was found to increase fibroblast viability. Additionally, we observed the same differential regulation of these two MIF family proteins in human adipose tissue in septic vs healthy patients. Taken together, these data suggest an inverse relationship between adipocyte MIF and MIF‐2 expression during systemic inflammation, with the downregulation of MIF‐2 in fat tissue potentially increasing pro‐inflammatory macrophage polarization to further drive adipose inflammation.

Link between aging and atheroprotection in Mif-deficient atherosclerotic mice

“…While it primarily promotes leukocyte infiltration and vascular inflammation in young and middle-aged mice through its chemokine-like inflammatory activities as shown in numerous studies (10,18,20,21,33), and may attenuate the proliferation or survival of anti-inflammatory plaque macrophage subtypes; these effects may be lost or become overcompensated in the aged vessel wall. Alternatively, MIF may have a polarizing effect on plaque macrophages from an anti-to a pro-inflammatory phenotype, as observed previously in the context of oncogenesis or adipose tissue-associated macrophages (49,50). A detailed future investigation of MIF effects on the recruitment, survival, or polarization of selective vascular wall macrophage sub-populations, including the involved MIF receptor pathways, would thus be warranted.…”

“…Global gene deficiency may cause various compensatory mechanisms and MIF has been assigned both extracellular inflammatory and intracellular homeostatic activities (7). Moreover, the MIF-homolog D-dopachrome tautomerase (D-DT)/MIF-2 shares some activities with MIF (60), while distinct effects have also been noted (50). MIF-2 has not been studied in atherosclerosis, but (compensatory) effects of MIF on MIF-2 gene expression have been observed in a cancer cell line (61).…”

Exosomal MIF Derived From Nasopharyngeal Carcinoma Promotes Metastasis by Repressing Ferroptosis of Macrophages

“…TAMs exhibit strong M2 polarization in most malignant tumors, which may be attributed to this "iron supply" feature that promotes cancer (Cairo et al, 2011). Bong-Sung Kim et al found that the downregulation of MIF-2 in fat tissue potentially increased pro-inflammatory macrophage polarization (Kim et al, 2020). Gabriela F. de Souza et al demonstrated that MIF was expressed during RSV infection and controlled the release of pro-inflammatory cytokines from macrophages in an in vitro model.…”

Mesenchymal Stem Cells in Adipose Tissue and Extracellular Vesicles in Ovarian Cancer Patients: A Bridge toward Metastatic Diffusion or a New Therapeutic Opportunity?

“…ADSCs account for about 20% of the SVF and have a close relationship with the other SVF cells regulated by a high paracrine activity, based on several mediators [14]. Local and general conditions, such as obesity, inflammation, sepsis, ischemia-reperfusion injury, tissue repair, and cancer, influence the secretory activity of ADSCs in the microenvironment [15][16][17][18].…”