Evolving complexity of MIF signaling

Abstract

Macrophage migration inhibitory factor (MIF) is a cytokine expressed in various cell types, including hematopoietic, epithelial, endothelial, mesenchymal and neuronal cells. Altered MIF expression has been associated with a multitude of diseases ranging from inflammatory disorders like sepsis, lupus and rheumatoid arthritis to organ pathologies such as heart failure, myocardial infarction, acute kidney injury, organ fibrosis and a number of malignancies. The implication of MIF in these diseases was supported by numerous animal studies. MIF acts in an autocrine and paracrine manner via binding and activating the receptors CD74/CD44, CXCR2, CXCR4 and CXCR7. Upon receptor binding, several downstream signaling pathways were shown to be activated in vivo, including ERK1/2, AMPK and AKT. Expression of MIF receptors is not uniform in various cells, resulting in differential responses to MIF across various tissues and pathologies. Within cells, MIF can directly bind and interact with intracellular proteins, such as the constitutive photomorphogenic-9 (COP9) signalosome subunit 5 (CSN5), p53 or thioredoxin-interacting protein (TXNIP). D-dopachrome tautomerase (D-DT or MIF-2) was recognized to be a structural and functional homolog of MIF, which could exert overlapping effects, raising further the complexity of canonical MIF signaling pathways. Here, we provide an overview of the expression and regulation of MIF, D-DT and their receptors. We also discuss the downstream signaling pathways regulated by MIF/D-DT and their pathological roles in different tissue, particularly in the heart and the kidney.

Introduction

Macrophage migration inhibitory factor (MIF) was definitively cloned and described as a factor amplifying the systemic inflammatory response to endotoxin treatment in 1993 [1]. Since then, MIF has been shown to play a crucial role in mediating resistance to different pathogens [[2], [3], [4], [5]] and driving various types of immune and autoimmune diseases [6,7]. MIF was also shown to be up-regulated in numerous types of malignancies and its expression correlates with the disease progression [8]. MIF exerts its biological functions in an autocrine and paracrine way [[9], [10], [11], [12], [13]] via the receptors CD74, CXCR2, CXCR4, and CXCR7 [[14], [15], [16]]. Upon MIF binding, CD74 does not induce signaling alone but requires the recruitment of CD44 or CXCR receptors [17]. There are several possible complexes formed between these receptors, including CD74/CD44 [[17], [18], [19]], CD74/CXCR2 [15], CD74/CXCR4 [20] and CD74/CXCR4/CXCR7 [16]. Up till now, it is not completely clear whether CD44 is also involved in the receptor complexes of CD74 with the CXCRs. Evidence for the induction of MIF signaling solely via CXCR7 was reported recently [21]. Tissue specific expression of MIF receptors and co-receptors (i.e. CD44) determine the tissue responsiveness to MIF. Recently, the vestigial enzyme D-dopachrome tautomerase (D-DT) was recognized as a structural and functional MIF homolog, bringing to life the concept of a “MIF cytokine family” [22,23].

In the first part of this review, we provide a general overview of the structure of MIF protein, regulation of MIF gene transcription in different cell types and summarize the published data on D-DT. In the second part, we give an overview of the MIF and D-DT receptors, their intracellular interacting partners and the downstream signaling pathways. In the third part, we summarize the data about tissue-specific effects of MIF and D-DT signaling by taking the heart and the kidney as two examples. The important roles of MIF in (auto)inflammatory and malignant diseases were summarized in a number of excellent review articles [[24], [25], [26], [27]]. Here, we focus on the less well-understood and yet underappreciated roles of MIF signaling.