The Role of Macrophage Migration Inhibitory Factor (MIF) Family Proteins in Wound Repair and Obesity

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Obesity is a condition associated with chronic adipose tissue inflammation (CAI) and represents a risk factor for several diseases including type 2 diabetes mellitus (T2DM). Importantly, obese patients often show delayed wound repair and an increased risk of wound healing disorders which remains an unsolved issue, particularly in Plastic and Reconstructive Surgery. A strong body of evidence suggests that the chemokine-like inflammatory cytokine macrophage migration inhibitory factor (MIF) promotes obesity, T2DM, CAI, while inhibiting wound repair. In contrast, little is known about MIFs recently discovered homolog D-dopachrome tautomerase (DDT) in this context. Preliminary work by the applicants leading up to this proposal has provided evidence for a reciprocal regulation of MIF and DDT in adipose tissue of patients with acute wound healing disorders. Reciprocal MIF and DDT regulation in inflamed adipose tissue was observed in a murine LPS injection model and adipocytes were identified as the cellular source for differential MIF and DDT expression. Interestingly, the coincident up-regulation versus down-regulation of MIF and DDT, respectively, was seen to have a detrimental effect on wound repair in vitro. Furthermore, Only MIF regulated monocyte migration into LPS-injected adipose tissue via its receptors CXCR2 and CXCR4 while DDT did not appear to exhibit pro-migratory effects.Here we aim to comprehensively study the role of MIF and DDT in the context of CAI, insulin resistance and wound repair under obesity, applying murine in vivo models, patient tissue specimens, and mechanistic experiments. First, wildtype mice and mice with a global Ddt knockout will undergo a high fat diet (HFD) to investigate the hitherto unknown effect of DDT on obesity, insulin resistance and CAI. Next, mice with an adipose tissue-specific knockout of Mif and Ddt (or wildtype in the control) that are fed a HFD will undergo incisional and excisional wounding to characterize the precise role of adipose tissue-derived MIF and DDT on wound repair under obese conditions. We predict that the inverse role of MIF and DDT that was observed in our preliminary experiments also will apply to our in vivo models. To establish potential therapeutic strategies, the feasibility of administering recombinant MIF/DDT protein and/or MIF/DDT neutralizing antibodies will additionally be studied in the in vivo models. In a third part, the experimental in vivo studies will be complemented by evaluation of primary human adipose tissue samples of obese and lean individuals. To this end, MIF- and DDT-dependent wound healing processes will be examined using in vitro co-culture assays of the adipose tissue samples and human fibroblasts/keratinocytes. Lastly, to identify the receptors contributing to MIF and DDT interactions, mechanistic studies will be performed to address the role of CD74, CD44, CXCR2, and/or CXCR4 as well as the relevant signaling pathways.