CD37 HLI data

Peripheral artery disease (PAD) affects >14 million Americans, and its most severe form, critical limb-threatening ischemia (CLTI), is marked by persistent inflammation and impaired skeletal muscle repair. Tetraspanins organize immune receptor signaling, but their roles in CLTI remain incompletely defined. Here, we focused on the leukocyte tetraspanin CD37 prompted by transcriptomic evidence of CD37 upregulation in human PAD gastrocnemius muscle. Using deconvolution-based immune profiling of human muscle RNA-seq alongside a murine hindlimb ischemia model, we show that CD37 is closely linked to immune infiltration in PAD and aligns most strongly with inflammatory macrophage programs. Cd37 deficiency enhanced perfusion recovery and improved muscle histologic repair, accompanied by increased myofiber maturation. Transcriptomic analysis of post-ischemic muscle revealed a shift toward reparative remodeling pathways, including extracellular matrix turnover, with attenuation of inflammatory cytokine and interferon-associated signatures. Tissue phenotyping and ex vivo studies further supported macrophage reprogramming toward a more pro-resolving state in Cd37-/- conditions, including enrichment of CD163+ macrophages and reduced production of key inflammatory mediators after LPS stimulation. Collectively, these findings identify CD37 as a regulator of macrophage-driven inflammation that limits revascularization and skeletal muscle regeneration after ischemic injury, supporting its potential as a therapeutic target to improve tissue recovery in CLTI.