Nociceptive sensory nerves induce an IL4Rα^hi anti-inflammatory macrophage subset that protects against kidney ischemia-reperfusion injury.

Abstract

Transient receptor potential cation channel subfamily V member 1⁺ (TRPV1⁺) sensory nerves, usually involved in transmitting pain and itch signals, densely innervate the kidney. Since the kidney is not a classic pain-sensitive organ, the roles of these sensory nerves beyond pain perception remain unknown. Here, we reveal a neuroimmune axis wherein TRPV1⁺ nociceptive sensory neurons protect against kidney ischemia-reperfusion (I/R) injury by inducing an anti-inflammatory macrophage subset. We employed reporter mice to visualize TRPV1⁺ nociceptive sensory nerves and used retrograde neuronal tracing to identify the activation of kidney-innervating TRPV1⁺ neurons during kidney ischemia/reperfusion injury. To examine their function, we applied multiple nociceptor ablation strategies (genetic and chemical) and activation approaches. Macrophage responses were analyzed using flow cytometry and RNA sequencing, while molecular signaling pathways were investigated with pharmacological inhibitors and in vitro stimulation assays. Urinary calcitonin gene-related peptide (CGRP) levels and macrophage profiles were also assessed in post-nephrectomy patients to validate clinical relevance. Nociceptive sensory nerves are activated by inflammation during kidney ischemia/reperfusion injury and initiate protective anti-inflammatory programs by releasing CGRP, which signals through Receptor Activity Modifying Protein 1 (RAMP1) receptors on macrophages to induce a unique interleukin 4 receptor alpha (IL4Rα^hi) population via cAMP PKA-CREB-dependent pathway. CGRP synergizes with IL-4 to promote the anti-inflammatory and pro-healing function of macrophages. Elevated urinary CGRP levels correlated with reduced kidney injury markers (KIM-1 and NGAL) and higher proportions of anti-inflammatory macrophages in post nephrectomy patients. Our findings redefine nociceptors as active regulators of kidney inflammation and homeostasis, leveraging CGRP to convert macrophages into anti-inflammatory phenotypes to protect against kidney injury, offering new therapeutic opportunities for AKI.