Nociceptive sensory nerves induce an IL4Rαhi anti-inflammatory macrophage subset that protects against kidney ischemia-reperfusion injury [DRG_RNAseq]

Kidney is not a classic pain-sensitive organ but innervated by dense transient receptor potential cation channel subfamily V member 1 (TRPV1+) nociceptive sensory nerves, indicating potential regulatory functions of these nerves beyond pain perception that remains unknown. Macrophage-mediated inflammation is a critical step in the pathophysiology of AKI. Here, we reveal a neuroimmune axis wherein TRPV1+ nociceptive sensory neurons protect against kidney ischemia-reperfusion (I/R) injury by orchestrating macrophage polarization. The renal inflammation level is closely monitored by nociceptive sensory nerves. These nerves activate and initiate reparative programs to alleviate I/R injury by releasing calcitonin gene-related peptide (CGRP), which signals through Receptor Activity Modifying Protein 1 (RAMP1)/ Calcitonin Receptor-Like Receptor (CALCRL) receptors on macrophages to induce a unique interleukin 4 receptor alpha (IL-4Rαhi) population via cAMP-PKA-CREB-dependent pathway. CGRP synergizes with IL-4 to promote the anti-inflammatory and pro-healing function of macrophages, establishing a feedforward loop for macrophage repolarization. Clinically, elevated urinary CGRP levels correlated with reduced kidney injury markers and higher proportions of anti-inflammatory macrophages in post-nephrectomy patients. Our findings revealed a new role of renal sensory nerves as a critical regulator of renal repair through neuroimmune crosstalk, offering therapeutic opportunities for AKI.