Abstract
Macrophage migration inhibitory factor (MIF) is a pleiotropic cytokine and has been implicated in inflammatory diseases. However, little is known about the regulation of MIF in adipose tissue and its impact on wound healing. The aim of this study was to investigate MIF expression in inflamed adipose and determine its role in inflammatory cell recruitment and wound healing. Adipose tissue was harvested from subcutaneous adipose tissue layers of 24 healthy subjects and from adipose tissue adjacent to acutely inflamed wounds of 21 patients undergoing wound debridement. MIF protein and mRNA expression were measured by ELISA and RT-PCR. Cell-specific MIF expression was visualized by immunohistochemistry. The functional role of MIF in cell recruitment was investigated by a chemotaxis assay and by flow cytometry of labeled macrophages that were injected into Mif –/–and wildtype mice. Wound healing was evaluated by an in vitro scratch assay on human fibroblast monolayers. MIF protein levels of native adipose tissue and supernatants from acutely inflamed wounds were significantly elevated when compared to healthy controls. MIF mRNA expression was increased in acutely inflamed adipose tissue indicating the activation of MIF gene transcription in response to adipose tissue inflammation. MIF is expressed in mature adipocytes and in infiltrated macrophages. Peripheral blood mononuclear cell migration was significantly increased towards supernatants derived from inflamed adipose tissue. This effect was partially abrogated by MIF-neutralizing antibodies. Moreover, when compared to wildtype mice, Mif –/–mice showed reduced infiltration of labeled macrophages into LPS-stimulated epididymal fat pads in vivo. Finally, MIF antibodies partially neutralized the detrimental effect of MIF on fibroblast wound healing. Our results indicate that increased MIF expression and rapid activation of the MIF gene in fat tissue adjacent to acute wound healing disorders may play a role in cell recruitment to the site of inflammation and wound healing.
Highlights
Macrophage migration inhibitory factor (MIF) was initially described in the context of delayed-type hypersensitivity [1]
MIF protein levels are increased in native subcutaneous adipose tissue from IAT
Fat tissue is a critical organ in body homeostasis and the increasing number of obese patients with impaired wound healing has generated significant interest in the function of adipose tissue during wound repair [13, 21]
Summary
Macrophage migration inhibitory factor (MIF) was initially described in the context of delayed-type hypersensitivity [1]. Stored in preformed intracellular pools, MIF release is induced by pro-inflammatory factors such as tumor necrosis factor (TNF)-α, lipopolysaccharide (LPS) or interferon (IFN)-γ [2]. MIF expression in adipose tissue was first reported in the epididymal fat pad of rats and in 3T3-L1 cells, a commonly used murine preadipocyte cell line [3]. Cultured human adipocytes and preadipocytes were found to express a significant amount of MIF which correlated with the body mass index (BMI) of the donor [4]. In 3T3-L1 cells, MIF has an impact on adipogenesis through inhibition of clonal expansion and expression of CCAAT/enhancer binding protein (C/EBP) α and C/EBP δ [5]. MIF mRNA upregulation is mediated by TNF-α through tyrosine-kinase dependent pathways in 3T3-L1 cells [6]
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