Injuries to skeletal muscle are among the most common injuries in civilian and military populations, accounting for nearly 60% of extremity injuries. The standard of care for severe extremity injury has been focused upon limb salvage procedures and the utilization of tissue grafts or orthotics in conjunction with rehabilitation to avoid amputation. Nonetheless, many patients have persistent strength and functional deficits that permanently impact their quality of life. Preclinical and clinical studies have shown that partial restoration of functional skeletal muscle tissue following injury can be achieved by the implantation of a biologic scaffold composed of extracellular matrix (ECM). These favorable outcomes are mediated, at least in part, through local immunomodulation. The mechanisms underlying this immunomodulatory effect, however, are poorly understood. The present study investigates a potential mechanistic driver of the immunomodulatory effects; specifically, the effect of selected ECM components upon inflammation resolution and repair. Results show that the host response to skeletal muscle injury is profoundly altered and functional recovery decreased in il33^−/− mice compared to age- and sex-matched wildtype counterparts by 14 days post-injury. Results also show that IL-33, contained within matrix-bound nanovesicles (MBV), supports skeletal muscle regeneration by regulating local macrophage activation toward a pro-remodeling phenotype via canonical and non-canonical pathways to improve functional recovery from injury compared to untreated il33^−/− counterparts. Taken together, these data suggest that MBV and their associated IL-33 cargo represent a novel homeostatic signaling mechanism that contributes to skeletal muscle repair.

骨骼肌损伤是平民和军人中最常见的损伤之一，占四肢损伤的近 60%。严重肢体损伤的护理标准侧重于保肢手术以及使用组织移植物或矫形器与康复相结合以避免截肢。尽管如此，许多患者仍存在持续的力量和功能缺陷，永久影响他们的生活质量。临床前和临床研究表明，通过植入由细胞外基质（ECM）组成的生物支架可以实现损伤后功能性骨骼肌组织的部分恢复。这些有利的结果至少部分是通过局部免疫调节来介导的。然而，人们对这种免疫调节作用的机制知之甚少。本研究调查了免疫调节作用的潜在机制驱动因素；具体来说，选定的 ECM 成分对炎症消退和修复的影响。结果表明，与年龄和性别匹配的野生型小鼠相比， IL33 ^-/−小鼠在受伤后 14 天时，宿主对骨骼肌损伤的反应发生了深刻的改变，功能恢复也有所下降。结果还表明，与未经治疗的il33相比，基质结合纳米囊泡 (MBV) 中包含的 IL-33 通过规范和非规范途径调节局部巨噬细胞活化至促重塑表型，从而支持骨骼肌再生，从而改善损伤后的功能恢复^−/−对应物。总而言之，这些数据表明 MBV 及其相关的 IL-33 货物代表了一种有助于骨骼肌修复的新型稳态信号机制。