Immune Protein CD37 Blocks Leg Muscle Healing in Artery Disease

Peripheral artery disease, or PAD, is one of the most common and least discussed vascular conditions in the world, affecting more than 14 million Americans alone. In its most advanced and dangerous form, known as chronic limb-threatening ischemia, blood flow to the legs becomes so restricted that muscle tissue starves, wounds refuse to heal, and amputation becomes a real possibility. For decades, clinicians have focused on restoring blood supply through bypass surgery or stents, yet many patients still recover poorly even after revascularization succeeds. A new study published in the Journal of Translational Medicine by Min Dai, Bernardo Gindri Dos Santos, and colleagues at the Cardiovascular Research Center of New York University Grossman School of Medicine suggests that a single immune surface protein may be quietly sabotaging that recovery, and that removing it could unlock dramatically better healing.

The protein in question is CD37, a member of the tetraspanin family. Tetraspanins are small four-pass transmembrane proteins that do not act as classical receptors themselves. Instead, they function as molecular organizers, clustering immune receptors into microdomains on the cell surface and fine-tuning the signals those receptors deliver. On leukocytes, CD37 has been implicated in B cell signaling, phagocytosis, and inflammatory regulation, but its role in ischemic tissue injury had remained largely unexplored. The NYU team began with a simple observation drawn from human tissue: in gastrocnemius muscle samples from patients with PAD, CD37 expression was markedly elevated, hinting that this immune organizer might be part of the disease process rather than a bystander.

To understand what that elevation meant, the researchers applied deconvolution-based immune profiling to transcriptomic data from human PAD muscle. This computational approach infers the composition of immune cell populations within bulk tissue gene expression data, allowing the team to link CD37 levels to specific immune programs. The results were striking. CD37 expression correlated strongly with overall immune infiltration, with a correlation coefficient of 0.51 and a p-value of 0.0002. More tellingly, its strongest relationship was with inflammatory macrophage programs, showing a correlation of 0.48 with a p-value of 0.0003. Macrophages, the tissue-resident scavenger cells capable of both fueling and resolving inflammation, appeared to be the cell type most tightly linked to CD37 abundance in failing human muscle.

Correlation alone cannot establish causation, so the team turned to an experimental system. They used the murine hindlimb ischemia model, a standard technique in which blood flow to a mouse’s hind leg is surgically interrupted, mimicking the ischemic injury of severe PAD. They then compared wild-type mice with genetically engineered mice lacking CD37 entirely, known as Cd37 knockout mice. Over the following weeks, the researchers measured perfusion recovery using laser-based blood flow imaging, examined skeletal muscle histology under the microscope, and profiled gene expression in the recovering tissue. The differences between the two groups were immediate and substantial.

The knockout mice revascularized far faster than their normal counterparts. By the key recovery timepoint, Cd37-deficient animals had achieved 87.6 percent reperfusion on average, compared with only 62.9 percent in wild-type mice, a difference that reached statistical significance at p less than 0.04. Blood flow, however, was only part of the story. When the researchers examined the muscle itself, they found that the knockout mice had rebuilt far more of their damaged tissue. Mature muscle fibers made up 77.9 percent of the recovered tissue in CD37-deficient animals versus just 46.7 percent in wild-type controls, with a p-value below 0.02. In other words, removing CD37 did not merely restore circulation; it allowed the muscle to genuinely regenerate rather than degenerate into scar tissue and fat.

To dissect the molecular mechanisms behind this accelerated healing, the team performed RNA sequencing on post-ischemic muscle from both groups. The analysis identified 594 differentially expressed genes at an adjusted p-value threshold of less than 0.05, a substantial transcriptional rewiring driven by the absence of a single surface protein. Pathway analysis revealed a coherent pattern. In the knockout muscle, genes related to muscle mass maintenance and collagen degradation were upregulated, suggesting active tissue rebuilding and clearance of fibrotic deposits. Conversely, pathways governing mitochondrial oxidative metabolism and proinflammatory signaling were downregulated. That the metabolic machinery of the muscle shifted away from oxidative programs may seem counterintuitive, but it likely reflects a reduced burden of inflammatory stress, which is known to distort mitochondrial function in ischemic tissue.

The most compelling findings emerged when the researchers integrated their RNA module scoring with immunohistochemistry, staining tissue sections to identify specific immune cell populations. This combined approach revealed that CD37 deficiency was associated with a fundamental reprogramming of macrophages toward a resolution phenotype. The knockout muscle contained macrophages with higher proresolving signatures and lower inflammatory signatures, and it harbored increased numbers of CD163-positive macrophages, a marker classically associated with anti-inflammatory, tissue-repairing macrophage states. In essence, the immune environment of the healing muscle had flipped from one that attacks damaged tissue to one that cleans up and rebuilds it.

To confirm that this shift originated in the macrophages themselves rather than being a secondary effect of the healthier tissue environment, the team isolated bone marrow-derived macrophages from both mouse groups and stimulated them ex vivo. Macrophages lacking CD37 secreted significantly lower levels of inflammatory cytokines and chemokines, the chemical messengers that recruit and activate additional immune cells and amplify tissue-damaging inflammation. This cell-autonomous result strengthens the causal chain: CD37 on macrophages directly promotes their inflammatory behavior, and that behavior, in turn, impairs the revascularization and regeneration of ischemic muscle.

The translational implications are considerable. Current therapies for chronic limb-threatening ischemia, including surgical bypass, angioplasty, and drug-eluting stents, address the plumbing of the disease but often leave the inflammatory biology untouched. Anti-inflammatory approaches to cardiovascular disease have gained momentum in recent years, but targeting inflammation broadly carries infection risks. CD37 offers something more precise: a surface molecule on immune cells whose removal shifts macrophages toward resolution without eliminating them. Notably, CD37 is already a validated target in oncology, with anti-CD37 antibody therapies in clinical development for B cell malignancies, which means the immunomodulatory toolkit for this protein is further along than for most novel targets. Repurposing or adapting those strategies for vascular medicine is a plausible next step, though the authors and outside observers alike would caution that a genetically engineered mouse is a long way from a diabetic patient with a non-healing foot ulcer.

There are also important caveats embedded in the data. The human findings are associative, drawn from transcriptomic correlations rather than direct functional experiments in patients. The mouse studies used complete knockout animals, so the effects of partial or transient CD37 inhibition remain unknown, as do potential consequences for the immune functions CD37 serves elsewhere, including B cell development and antitumor surveillance. The study was funded by the National Institutes of Health under grant R01HL167917 and by an American Heart Association postdoctoral fellowship, and the authors report no competing interests. Still, the convergence of human association, mouse genetics, transcriptomics, histology, and ex vivo cell biology makes a unusually coherent case. If future work confirms that blocking CD37 in patients with critical limb-threatening ischemia can tip their macrophages toward resolution, a protein once studied mainly by immunologists could become an unexpected lever for saving limbs, and the millions of people living with the silent narrowing of their leg arteries may finally gain a therapy that heals muscle, not just vessels.

Subject of Research: The role of the leukocyte tetraspanin CD37 in inflammation, revascularization, and skeletal muscle recovery in peripheral artery disease

Article Title: CD37 impairs revascularization and muscle recovery in peripheral artery disease

Article References: Dai, M., Gindri Dos Santos, B., Wu, J., Ferreira, E., Li, Z., Biswas, B., Schlamp, F., Boothman, I., & Barrett, T. J. (2026). CD37 impairs revascularization and muscle recovery in peripheral artery disease. Journal of Translational Medicine. https://doi.org/10.1186/s12967-026-08799-3

Image Credits: AI Generated

DOI: 10.1186/s12967-026-08799-3

Keywords: peripheral artery disease, CD37, tetraspanin, macrophages, inflammation, hindlimb ischemia, revascularization, muscle regeneration, critical limb-threatening ischemia, immune reprogramming, translational medicine, cytokines