Interleukin-33-Producing Stromal Cells Mediate Crosstalk Between Neuronal and Regulatory T Cells in Murine Skeletal Muscle

Abstract

A distinct population of regulatory T cells (Tregs) that accumulates in injured skeletal muscle helps control inflammation and enhances muscle regeneration. Muscle-localized Tregs express high levels of ST2, which encodes the receptor for the alarmin IL-33. The signaling of IL-33 through ST2 has been shown to promote Treg proliferation and support muscle repair. Here, we found that the primary IL-33 producers in mouse skeletal muscle are a subset of mesenchymal stromal cells (MSCs) expressing the markers Sca-1 and PDGFRα. We observed that IL-33-producing MSCs are often closely associated with peripheral nerve bundles as well as small-diameter sensory fibers. Population- and single-cell RNA-seq analysis revealed that the receptor for a pain-related neuropeptide, calcitonin gene-related peptide (CGRP), is expressed in IL-33+ cells. Furthermore, in vivo pharmacological perturbations suggested a role for CGRP in modulating IL-33 production in mouse skeletal muscle MSCs, thereby revealing the presence of a sensory neuron-immune interaction within the skeletal muscle environment that is mediated by IL33+ stromal cells.