Group 2 innate lymphoid cells regulate nociceptive and gait functions of the peripheral nervous system

The peripheral nervous system (PNS) is involved in nociception and gait. The contribution of PNS-resident immune cells to these functions is not fully understood. We identify group 2 innate lymphoid cells (ILC2s) as a distinct immune cell population resident within the PNS, having a unique gene profile facilitating neuron - ILC2 crosstalk. ILC2-deficient mice show PNS dysfunction, characterized by increased pain sensitivity and gait anomalies attributed to structural abnormalities in the sciatic nerves. ILC2s can communicate with DRG neurons via IL-13 signaling pathway to maintain nerve structure integrity and pain thresholds. Loss of IL-13 receptor signaling in the neurons results in a phenotype similar to ILC2-deficient mice. Intrathecally administered IL-13 rescues hypersensitivity and gait defects in ILC2-deficient mice, thereby imparting a therapeutic importance to this signaling pathway. Together, this study identifies a previously unknown function for ILC2s in regulating the nerve structural integrity and nociceptive functions of the PNS.