Department of Vascular Biology, Institute for Stroke and Dementia Research

Project description:

Atherosclerotic cardiovascular disease (CVD) remains the leading cause of death worldwide. Despite major advances in prevention and risk factor management, its prevalence continues to rise in aging societies. Atherosclerosis is a lipid-triggered inflammatory condition of the arterial wall, driven by atherogenic cytokines and chemokines that sustain leukocyte and platelet recruitment to the vessel wall, promoting plaque progression, rupture, and atherothrombosis. Both the landmark CANTOS trial (IL-1β) and the more recent ZEUS trial (IL-6) were neutral or negative overall, with increased rates of serious infections in both. This highlights the need for more selective anti-inflammatory targets. Chemokines are promising candidates for such vascular-specific strategies without broad immunosuppression — though therapeutic targeting remains challenging given the complex network comprising about 50 ligands and 20 receptors. Macrophage migration inhibitory factor (MIF) and its paralog MIF-2 (D-dopachrome tautomerase) are inflammatory cytokines that, despite lacking the conserved cysteine motif of classical chemokines (CKs), signal through chemokine receptors CXCR2 and CXCR4 and promote atherogenic leukocyte recruitment — establishing both as atypical chemokines (ACKs). Work from the host laboratory has identified a "chemokine interactome," in which MIF forms heteromeric complexes with CKs such as the platelet-derived CXCL4L1, modulating its inflammatory, leukocyte-recruiting, and thrombotic functions. While interactions among CKs are increasingly well characterized, ACK–CK and ACK–ACK interactions — and their pharmacological accessibility — remain largely unexplored. This project hypothesizes that MIF(-2)–chemokine interactions fine-tune the inflammatory response during atherogenesis and represent an underexploited therapeutic entry point. Building on this rationale, the project will also explore targeting strategies designed to interfere selectively with MIF(-2)-driven signaling while sparing homeostatic chemokine axes. Given that MIF and MIF-2 are similarly implicated in other chronic inflammatory conditions, including neuroinflammation, insights gained here may extend beyond atherosclerosis to a broader range of MIF(-2)-driven disease contexts.