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

ABSTRACT: 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.

ORGANISM(S): Mus musculus

PROVIDER: GSE299312 | GEO | 2026/05/28

REPOSITORIES: GEO

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

Project description: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.

2026-05-28 | GSE299314 | GEO

CGRP signaling Links Tumor-Associated Pain to Immune Evasion in Oral Squamous Cell Carcinoma

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Nociceptive innervation limits tertiary lymphoid structures to promote lung cancer

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Sensory nerve-derived CGRP controls osteoclastogenesis by limiting macrophage bioenergetics in bone repair

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2024-02-21 | GSE253063 | GEO

The neuroimmune CGRP-RAMP1 axis tunes cutaneous adaptive immunity to the microbiota.

2024-02-21 | GSE253041 | GEO

Dermal TRPV1 innervations engage a macrophage and fibroblast containing pathway to activate hair growth [dataset2]

Project description:Pain, detected by nociceptors, is an integral part of injury, yet whether and how it can impact tissue physiology and recovery remain understudied. Here we applied chemogenetics in mice to locally activate dermal TRPV1 innervations in naïve skin and found it triggered new regenerative cycling by dormant hair follicles (HFs).This was preceded by rapid apoptosis of dermal macrophages, mediated by the neuropeptide calcitonin gene-related peptide (CGRP). TRPV1 activation also triggered a macrophage-dependent induction of Spp1-expressing dermal fibroblasts. The neuropeptide CGRP andSpp1were essential for the nociceptor-triggered hair growth. Finally, we show that epidermal abrasion injury induced Spp1-expressing dermal fibroblasts and hair growth via a TRPV1 neuron and CGRP dependent mechanism.Collectively, these data demonstrate a role for TRPV1 nociceptors in orchestrating a macrophage and fibroblast-supported mechanism to promote hair growth, and enabling the efficient restoration of this mechano- and thermo-protective barrier after wounding.

2024-05-10 | GSE266028 | GEO

Dermal TRPV1 innervations engage a macrophage and fibroblast containing pathway to activate hair growth [dataset1]

2024-05-10 | GSE266027 | GEO

Calcitonin gene related peptide negatively regulates alarmin-driven type 2 innate lymphoid cell responses

Project description:Neuroimmune interactions have emerged as critical modulators of allergic inflammation, and type 2 innate lymphoid cells (ILC2s) are an important cell type for mediating these interactions. Here, we show that ILC2s expressed both the neuropeptide CGRP (Calcitonin Gene-Related Peptide) and its receptor. CGRP potently inhibited alarmin-driven type 2 cytokine production and proliferation by lung ILC2s both in vitro and in vivo. CGRP induced marked changes in ILC2 expression programs in vivo and in vitro, attenuating alarmin-driven proliferative and effector responses. A distinct subset of ILCs scored highly for a CGRP-specific gene signature after in vivo alarmin stimulation, suggesting CGRP regulated this response. Finally, we observed increased ILC2 proliferation and type 2 cytokine production and exaggerated responses to alarmins in mice lacking the CGRP receptor. Together, these data indicate that endogenous CGRP is a critical negative regulator of ILC2 responses in vivo.

2019-10-08 | GSE136154 | GEO

Upregulation of the neuropeptide receptor calcitonin receptor-like in the spinal cord via MLL2 in a mouse model of paclitaxel-induced peripheral neuropathy

Project description:Chemotherapy-induced peripheral neuropathy (CIPN) is a prevalent and severe side effect affecting cancer patients undergoing paclitaxel treatment. Growing evidence underscores the pivotal role of calcitonin-related peptide (CGRP) in the development of CIPN. Repeated administration of paclitaxel induces alterations in CGRP release from sensory neurons within the dorsal root ganglia (DRG). The density of the CGRP receptor is most prominent in the spinal horn, where it overlaps with the distribution of CGRP. However, the impact of chemotherapy medication on expression of the CGRP receptor in the spinal cord remains unclear, as well as the potential therapeutic benefits of a CGRP receptor antagonist in an animal model of CIPN. Using a mouse model of paclitaxel-induced mechanical hypersensitivity, we show upregulation of Calcitonin receptor-like receptor (Calcrl) mRNA expression in the spinal cord, an event that occurred in association with upregulation of the H3K4 methyltransferase MLL2. This effect of repeated paclitaxel administration was also linked to an increase in the recruitment of MLL2, thereby enhancing levels of the active mark H3K4me2 at the Calcrl promoter. Furthermore, administration of the CGRP receptor antagonist BIBN4096 mitigated mechanical and cold hypersensitivity in paclitaxel-treated mice. Together, these observations suggest the CGRP receptor in the spinal cord as a potential target for reducing paclitaxel-induced neuropathic pain in animal models.

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