Matrix bound nanovesicle-associated IL-33 activates a pro-remodeling macrophage phenotype via a non-canonical, ST2-independent pathway

Abstract

The regenerative healing response of injured skeletal muscle is dependent upon an appropriately timed switch from a local type-I to a type-II immune response. Biologic scaffolds derived from extracellular matrix (ECM) have been shown to facilitate a macrophage phenotype transition that leads to downstream site-appropriate functional tissue deposition and myogenesis. However, the mechanisms by which ECM directs the switching of immune cell phenotype are only partially understood. Herein, we provide the first evidence that matrix bound nanovesicles (MBV) embedded within ECM-scaffolds are a rich and stable source of interleukin-33 (IL-33), an alarmin/ cytokine with emerging reparative properties. We show that IL-33 encapsulated within MBV bypass the classical IL33/ST2 receptor signaling pathway to direct macrophage differentiation into the reparative, pro-remodeling M2 phenotype, which in turn facilitates myogenesis of skeletal muscle progenitor cells. Our results suggest the potential of IL-33 + MBV as a clinical therapy to augment the restorative efficacy of existing ECM-based and non-ECM based approaches.

Untangling Local Pro-Inflammatory, Reparative, and Regulatory Damage-Associated Molecular-Patterns (DAMPs) Pathways to Improve Transplant Outcomes

“…Several proteases can increase the activity of full-length IL-33 by cleaving off the nuclear localization domain and chromatin binding motif ( 154 , 156 ). We have also recently demonstrated that bio-active IL-33 is present in vesicles bound to the ECM of stromal cells where it is protected from proteolytic modification ( 157 ).…”

“…Numerous immune cells express varying levels of ST2. These include basophils, mast cells, eosinophils, group 2 innate lymphoid cells (ILC2s) ( 154 ), CD8 + ( 159 , 160 ), and CD4 + T cells ( 161 ), particularly Th2 cells and Treg ( 74 – 77 , 158 , 162 ), B cells ( 163 ), macrophages ( 78 , 157 , 163 ), and DC subsets ( 162 , 164 , 165 ). IL-33 acts on these cells to support type 2 responses dominated by the cytokines IL-5 and IL-13.…”

Agent-based model provides insight into the mechanisms behind failed regeneration following volumetric muscle loss injury

“…For example, will modulating the early inflammatory response or mitigating fibrotic pathways in VML injuries, or both, improve muscle regeneration and functional outcomes? A better understanding of these mechanisms is a prerequisite to the design of more efficacious regenerative therapeutics for VML repair [8,9,[21][22][23][24][25].…”

The Role of Extracellular Vesicles in the Pathogenesis and Treatment of Autoimmune Disorders

“…The location of EVs within the ECM can also dictate certain physiological processes such as differentiation and angiogenesis ( 21 ). During skeletal regeneration, matrix-bound EVs guide macrophage differentiation and downstream myogenesis of skeletal muscle progenitor cells ( 22 , 23 ). EVs can also be freely shed to travel through interstitial fluid to the lymph nodes or diffuse into the bloodstream ( 24 ).…”