Acute kidney injury affects more than 13.3 million people worldwide each year, prolongs hospital stays, and carries mortality ranging from roughly 10 percent to 80 percent depending on the population and the severity of injury. Survivors, particularly older adults and people with diabetes or hypertension, face elevated risks of chronic kidney disease. No pharmacological therapy has yet been approved to prevent the condition or speed recovery, which makes the identification of a protective neural pathway especially significant.

The team, led by Lei Wang and Xin Ma of the Chinese PLA General Hospital, applied the SHANEL clearing method to whole mouse kidneys and reconstructed the three-dimensional architecture of CGRP-positive sensory fibers with light-sheet microscopy. To confirm the imaging genetically, they crossed TRPV1-Cre mice with fluorescent reporter lines and used CUBIC clearing to visualize labeled fibers within the kidney. Retrograde tracing with pseudorabies virus and anterograde tracing with a viral vector converging on the same answer showed that each kidney receives its nociceptive supply predominantly from the ipsilateral T10 through L2 dorsal root ganglia, with little contribution from the vagal sensory ganglia.

Functional experiments established that this innervation is not a passive wiring diagram. Three independent depletion strategies, genetic ablation with diphtheria toxin in Trpv1-Cre mice, systemic chemical ablation with the TRPV1 agonist resiniferatoxin, and localized capsaicin treatment around the renal artery, each worsened outcomes after bilateral ischemia-reperfusion. Ablated animals showed higher serum creatinine and urea on day two, more tubular necrosis, dilation and cast formation, and by day twenty-eight increased interstitial collagen deposition indicating progressive fibrosis. Conversely, chemogenetic activation of T10-L2 nociceptors using a DREADD receptor improved both acute and chronic outcomes. The authors note that all formal mechanistic experiments were conducted in female mice, because exploratory studies in males produced high mortality that left too few survivors for adequately powered analysis, so the conclusions are restricted to females.

Among the neuropeptides the researchers quantified in kidney tissue, only CGRP, the calcitonin gene-related peptide, was abundant at baseline and rose after injury, and its expression increased in the cell bodies of kidney-innervating dorsal root ganglion neurons. Mice lacking CALCA-derived alpha-CGRP developed more severe acute and chronic injury after ischemia-reperfusion, while systemic CGRP supplementation beginning two days before surgery and continuing for two weeks protected wild-type mice and rescued the exaggerated injury caused by sensory denervation. Together these experiments identified CGRP as the key mediator linking nociceptors to kidney protection.

The cellular target turned out to be the innate immune system. Flow cytometry of renal leukocytes showed that sensory denervation specifically increased infiltration of CD11b-high monocytes and macrophages and neutrophils, without changing dendritic cells, B cells, or T cells. To test whether CGRP acts on monocytes and macrophages, the team generated mice with myeloid-specific deletion of Calcrl, which encodes a component of the CALCRL-RAMP1 CGRP receptor complex. These mice phenocopied sensory ablation, with amplified myeloid infiltration and worse kidney injury, and exogenous CGRP no longer reduced leukocyte infiltration or protected the kidney in them. Reducing monocytes and macrophages with a CSF1R inhibitor abolished the excess inflammation and injury, confirming these cells as the principal effectors.

Transcriptomic analysis of sorted renal monocytes and macrophages revealed the mechanism. Without CGRP signaling, the cells upregulated TNF, Toll-like receptor and NF-kappa-B pathway modules along with pro-inflammatory cytokine genes such as Tnf and Il1b and chemokine genes including Cxcl2 and Ccl3, with corresponding increases in protein measured in whole-kidney lysates. In cultured bone-marrow-derived macrophages, CGRP suppressed the response to lipopolysaccharide, but this suppression failed in receptor-deficient cells and was restored by forskolin, an adenylyl cyclase activator that bypasses the receptor. Giving forskolin to receptor-deficient mice in vivo normalized cytokine and chemokine production, reduced monocyte and neutrophil influx, and improved both acute and chronic kidney outcomes, placing the cAMP-PKA pathway downstream of CALCRL-RAMP1 in this axis.

The most clinically striking finding concerns vulnerable populations. In a biospecimen cohort of forty-eight nephrectomy samples from macroscopically normal cortical tissue, renal CGRP levels were significantly lower in kidneys from elderly patients and from patients with diabetes than in young and middle-aged reference patients, while hypertensive samples showed no significant difference. Matching mouse models, streptozotocin and high-fat diet-induced diabetes and natural aging at twenty months, recapitulated the reduced baseline CGRP and the blunted rise after injury, with statistical analysis confirming significant interactions between diabetes or age and ischemic injury.

When diabetic and aged mice were subjected to ischemia-reperfusion, CGRP supplementation reduced TNF, IL-1beta, CXCL2 and CCL3, curtailed infiltration of neutrophils, monocytes and macrophages, and improved functional and histological outcomes at both acute and chronic time points. The protective effects were more pronounced in these high-risk models than in young healthy animals, suggesting that impaired CGRP signaling contributes to the heightened susceptibility of aged and diabetic kidneys and that restoring the pathway could be most valuable precisely where risk is greatest.

The authors are careful about the limits of the work. The upstream signals that activate renal nociceptors and trigger CGRP release remain unidentified, the central projections of the fibers were not mapped, interactions with sympathetic outflow were not fully delineated, and TRPV1-lineage tools label only a subset of nociceptors. Whether the pathway behaves similarly in males is unknown. Even so, the study extends the emerging framework of nociceptor-mediated immune regulation to the kidney, establishes the anatomical and molecular basis of a sensory protective circuit, and nominates CGRP signaling through CALCRL-RAMP1 and cAMP-PKA in myeloid cells as a plausible strategy for treating acute kidney injury and halting its slide toward chronic kidney disease.

Subject of Research: A dorsal root ganglion-kidney neuroimmune circuit in which sensory neuron-derived CGRP protects against ischemia-reperfusion kidney injury and fibrosis via myeloid cell signaling

Article Title: Sensory neuron-derived CGRP ameliorates kidney injury and fibrosis via monocytes and macrophages

Article References: Wang, L., Li, H., Feng, J., Chen, J., Jia, T., Zhou, T., Wang, L., Tang, L., Zhang, X., & Ma, X. (2026). Sensory neuron-derived CGRP ameliorates kidney injury and fibrosis via monocytes and macrophages. Cell Research. https://doi.org/10.1038/s41422-026-01308-7

Image Credits: AI Generated

DOI: 10.1038/s41422-026-01308-7

Keywords: acute kidney injury, chronic kidney disease, nociceptors, CGRP, neuroimmune crosstalk, macrophages, ischemia-reperfusion, fibrosis, dorsal root ganglia, diabetes, aging, cAMP-PKA pathway

The review’s central thesis is that atopic dermatitis itch emerges from a dynamic, bidirectional conversation between keratinocytes, the dominant cells of the epidermis, and the sensory neurons that innervate the skin. When the epithelial barrier breaks down, whether through genetic vulnerability, environmental insult, or the mechanical trauma of scratching, stressed keratinocytes release a cocktail of damage-induced mediators known as alarmins. Chief among these are thymic stromal lymphopoietin (TSLP), interleukin-33 (IL-33), and interleukin-25 (IL-25). These signals do not merely recruit immune cells; they act directly on cutaneous nerve fibers, activating or sensitizing them and thereby amplifying itch transmission. The result is a self-reinforcing itch-scratch-injury cycle in which each bout of scratching further damages the barrier, releases more pruritogens, and entrenches neural hypersensitivity.

TSLP has emerged as perhaps the clearest example of epithelial-to-neural signaling. This keratinocyte-derived cytokine signals through a receptor complex comprising the TSLP receptor and the IL-7 receptor alpha subunit, potently activating dendritic cells and skewing immunity toward a type 2 profile dominated by Th2 cells, mast cells, and natural killer T cells. Serum TSLP is significantly elevated in patients with atopic dermatitis and correlates with disease severity. Crucially, work by Wilson and colleagues showed that calcium-dependent ORAI1/NFAT signaling in keratinocytes regulates TSLP release, and that TSLP in turn directly activates TRPA1-positive sensory neurons to induce itch. The same epithelial-neuronal crosstalk operates in airway epithelial cells, suggesting a mechanistic bridge that may help explain the atopic march, the progression from eczema to asthma and allergic rhinitis.

IL-33 presents a more complicated picture. It induces type 2 cytokines including IL-4, IL-5, and IL-13, synergizes with IL-4 to drive production of IL-31, a key pruritogen, and enhances histamine-induced itch through mast cell activation and IL-13 release. Its receptor, ST2, is expressed on dorsal root ganglion neurons in both humans and mice, and IL-33 can sensitize these neurons to IL-4- and IL-13-mediated signaling. In the spinal cord, IL-33/ST2 signaling activates an astrocytic JAK2-STAT3 pathway that engages the gastrin-releasing peptide (GRP) axis, a canonical spinal itch circuit whose serum levels correlate with disease severity and itch intensity in patients. Yet the review is candid about the limits of the evidence: some studies found no correlation between circulating IL-33 and pruritus severity, and neuronal-restricted IL-33 receptor signaling proved dispensable for itch in an AD-like mouse model. Genetic variants in the IL33 gene have been linked to itch severity, hinting that predisposition modulates the pathway, but a direct causal role in human AD itch remains unproven.

The strongest clinical case belongs to the type 2 cytokines IL-4 and IL-13. Both can directly activate mouse and human sensory neurons, and IL-4 additionally sensitizes neurons to a broad range of pruritogens. Mechanistically, chronic itch requires neuronal IL-4Ralpha-JAK1 signaling: deleting IL-4Ralpha or JAK1 specifically in sensory neurons markedly reduces scratching in mice, and JAK inhibition relieves recalcitrant chronic itch in patients unresponsive to conventional immunosuppressants. Recent work with human dorsal root ganglion neurons showed that IL-4, IL-13, and IL-33 sensitize neurons to both histaminergic and non-histaminergic pruritogens within just two hours of exposure, with IL-4 and IL-13 inducing a shared, cytokine-specific transcriptional program distinct from that triggered by other inflammatory stimuli. Type 2 immunity, in other words, has been co-opted by the nervous system itself.

Interleukin-31 stands out as the most thoroughly validated cytokine linking immune activation to neuronal itch signaling. Produced mainly by Th2 cells but also by basophils, macrophages, and, as recent evidence shows, M2-polarized macrophages in lesional skin, IL-31 signals through a receptor complex of IL-31 receptor A and the oncostatin M receptor. In a restricted population of IL-31RA-positive, TRPV1-positive, TRPA1-positive sensory neurons, IL-31 triggers intracellular calcium release and ERK activation. It also induces rapid STAT3 activation in these neurons, and STAT3 transcriptionally upregulates the IL-31 receptor itself, creating a feed-forward loop that amplifies sensitivity. Beyond the periphery, IL-31 induces expression of B-type natriuretic peptide (BNP), encoded by the NPPB gene, which transmits itch signals through natriuretic peptide receptor A in the spinal cord, and promotes axonal elongation and branching in small-diameter sensory neurons, providing a mechanistic explanation for the increased cutaneous nerve fiber density seen in chronic disease. The clinically approved antibody nemolizumab targets this axis.

The review also highlights periostin, a matrix protein secreted by dermal fibroblasts downstream of type 2 inflammation, as a conserved pruritogen that induces itch across mice, dogs, and non-human primates. Periostin binds integrin alphavbeta3 on sensory neurons, triggering extracellular calcium influx and spontaneous firing in an itch-related, TRPV1- and TRPA1-dependent manner, with BNP as a key neuropeptide effector. Remarkably, periostin also reciprocally induces keratinocyte-derived TSLP through the JAK2-STAT3 pathway, closing a feed-forward epithelial-neuronal loop. Serum periostin levels are elevated in patients and correlate with disease severity, positioning it as an emerging therapeutic target.

Neurotrophic factors and neuropeptides add a structural dimension to the story. Nerve growth factor (NGF) is markedly elevated in the stratum corneum of lesional skin, correlating with itch severity, erythema, xerosis, eosinophil counts, and serum lactate dehydrogenase, and blocking NGF signaling ameliorates dermatitis and scratching in the NC/Nga mouse model. Substance P, classically acting through the neurokinin-1 receptor, drives neurogenic inflammation and correlates with itch intensity and even depression scores, but recent work shows it can also evoke non-histaminergic itch by activating MRGPRX2 on mast cells and MRGPRA1 on sensory neurons, and it has displayed paradoxically protective, barrier-restoring effects in some experimental settings. Calcitonin gene-related peptide (CGRP) promotes keratinocyte proliferation and epidermal thickening, with atopic keratinocytes showing heightened CGRP responsiveness and exaggerated hyperplasia. Artemin, a glial cell line-derived neurotrophic factor, is upregulated in lesional skin downstream of both the aryl hydrocarbon receptor, activated by organic components of air pollution, and toll-like receptor signaling triggered by house dust mite, linking environmental exposures directly to sensory nerve sprouting and warmth-provoked itch.

Woven through all of these pathways is the JAK-STAT signaling cascade, which the authors identify as the most clinically validated convergence point between immune cytokines and pruritus. Lesional skin from patients shows broad activation of phosphorylated JAK1-3 and STAT2/3 across epidermal and dermal compartments, and a spontaneous mouse model with an epidermal JAK1 gain-of-function mutation demonstrated that keratinocyte-intrinsic JAK1 hyperactivation alone is sufficient to drive barrier dysfunction, chronic inflammation, and pruritus. JAK1 is also enriched in pruriceptive neurons, where it mediates IL-4, IL-13, and IL-31 signaling, and electrophysiological studies suggest that JAK1-selective inhibitors such as upadacitinib can directly modulate cortical neuronal activity, hinting at central neuromodulatory effects beyond immune suppression.

The conceptual payoff of the review is a continuum model of chronic itch. It begins as peripherally driven, epithelial-mediated signaling, but repeated stimulation progressively sensitizes sensory neurons and broadens their responsiveness until itch becomes partially decoupled from peripheral cues and increasingly reflects structural and functional remodeling within itch-processing circuits. The finding that even non-lesional skin of patients exhibits heightened cowhage-induced itch underscores that altered sensory responsiveness is an intrinsic feature of the disease, not merely a byproduct of visible inflammation. The authors argue that early intervention to interrupt repetitive itch-scratch cycles, before central sensitization and neuronal remodeling become entrenched, may be essential to prevent long-term chronicity, treatment resistance, and the psychological comorbidities that so often shadow this disease.

Subject of Research: Neuroimmune mechanisms of chronic itch in atopic dermatitis

Article Title: Pruritogenic mediators in atopic dermatitis: mechanisms of neurogenic crosstalk

Article References: Wong, L.-S., Yang, J.-H., Yen, Y.-T., & Yang, J.-L. (2026). Pruritogenic mediators in atopic dermatitis: mechanisms of neurogenic crosstalk. Journal of Cutaneous Immunology and Allergy, 9, Article 16460. https://doi.org/10.3389/jcia.2026.16460

Image Credits: AI Generated

DOI: 10.3389/jcia.2026.16460

Keywords: atopic dermatitis, chronic itch, pruritus, keratinocytes, sensory neurons, TSLP, IL-31, IL-4, IL-13, JAK-STAT signaling, neuropeptides, neuroimmune crosstalk

Hepatic fibrosis is the accumulation of excess extracellular matrix, chiefly collagen, that follows chronic liver injury from causes such as viral hepatitis, alcohol use, fatty liver disease, and cholestatic disorders. Left unchecked, it progresses to cirrhosis and dramatically raises the risk of hepatocellular carcinoma. At the center of the scarring process are hepatic stellate cells, quiescent vitamin A-storing cells that, when activated by inflammatory cues, transform into myofibroblast-like cells that pump out matrix proteins. The immune microenvironment surrounding these cells, particularly the behavior of macrophages, largely determines whether injury resolves or spirals into permanent scarring. Macrophages are famously plastic: they can polarize toward a classically activated M1 state, marked by production of tumor necrosis factor-alpha and interleukin-1 beta, or toward an alternatively activated M2 state, associated with transforming growth factor beta and tissue remodeling. Both extremes, paradoxically, can feed fibrosis, one by fueling inflammation and the other by driving matrix deposition.

What the new study adds is a nervous system connection to this immunological drama. The researchers began by examining liver tissue from cirrhotic and non-cirrhotic human subjects, with informed consent and ethical approval from Tangdu Hospital, and then modeled fibrosis in mice using two complementary approaches: repeated intraperitoneal injection of carbon tetrachloride, a hepatotoxin that causes oxidative injury, and a 3,5-diethoxycarbonyl-1,4-dihydrocollidine diet, which induces cholestatic damage. Across both human samples and both mouse models, NPY levels rose in fibrotic livers. Crucially, the source of that NPY was not the liver cells themselves but intrahepatic sympathetic nerves, identified through markers such as tyrosine hydroxylase. The finding places the sympathetic nervous system, the branch that mediates fight-or-flight responses, in direct molecular contact with the liver’s immune landscape.

The team next asked which cells were listening. NPY signals through a family of G protein-coupled receptors, and the investigators mapped their distribution carefully. Two of them, NPY1R and NPY2R, were significantly increased in fibrotic liver and localized specifically to hepatic macrophages, while the related NPY4R and NPY5R did not show the same pattern. This receptor specificity matters, because it narrows a broad neuropeptide signal down to a defined cellular target and suggests that the macrophage is the critical relay station between sympathetic nerve activity and fibrogenesis.

To test causality rather than mere correlation, the researchers turned to genetics and gene silencing. In NPY-knockout mice subjected to the fibrosis protocols, liver injury, collagen deposition, and inflammation were all significantly reduced. Flow cytometry and molecular profiling of the animals’ macrophages revealed that the deletion suppressed both M1 and M2 polarization, indicating that NPY was not simply tipping the balance between the two states but amplifying the entire profibrotic immune program. When the team silenced NPY1R or NPY2R in the liver in vivo using adeno-associated virus vectors, the protective phenotype was recapitulated, confirming that the receptors were the necessary conduits for NPY’s fibrogenic effects.

The mechanistic heart of the paper lies in the downstream signaling dissection, performed in vitro with bone marrow-derived macrophages. The researchers found that NPY engages a PI3K-dependent cascade in both polarization directions, but the pathways diverge at a key kinase node. For M1 polarization, NPY acting through NPY1R and NPY2R activates the PI3K-PAK1-c-Jun axis, with c-Jun, a component of the AP-1 transcription factor complex, driving the inflammatory gene program. For M2 polarization, the signal instead flows through PI3K-PAK1 to RSK, a ribosomal S6 kinase, promoting the alternative activation program. Blocking the corresponding receptors or the downstream kinases pharmacologically in vitro abolished these effects, allowing the authors to draw a solid, experimentally validated map from neuropeptide to receptor to kinase to transcription factor to macrophage phenotype.

The final link in the chain connects macrophages back to stellate cells. Polarized macrophages release a cocktail of profibrotic cytokines, including TNF-alpha, IL-1 beta, TGF-beta, and platelet-derived growth factor BB, which are well-established activators of hepatic stellate cells. By supercharging both macrophage states, NPY effectively raises the volume of the profibrotic conversation between immune cells and matrix-producing cells. The authors are careful to distinguish what has been proven from what remains plausible: the receptor-PI3K-PAK1 cascades are experimentally validated, whereas a direct NPY effect on stellate cells and the precise macrophage-stellate cell crosstalk remain putative, unvalidated interactions in their model. That transparency is a useful reminder of where the science currently stands.

The therapeutic implications are considerable. Current antifibrotic options are limited, and most strategies target downstream consequences of injury rather than upstream regulatory circuits. If sympathetic nerve-derived NPY is a genuine driver of fibrogenesis, then NPY1R and NPY2R become attractive drug targets, and receptor antagonists, some of which have already been developed for metabolic and cardiovascular research, could in principle be repurposed or refined. The dual role of NPY in pushing macrophages toward both inflammatory and profibrotic states suggests that receptor blockade might dampen fibrosis through two mechanisms simultaneously. At the same time, the systemic importance of NPY in appetite regulation, vascular tone, and stress physiology means that any clinical strategy would need to navigate a narrow therapeutic window, likely favoring targeted delivery to the liver or selective peripheral receptor antagonism over systemic neuropeptide depletion.

The study also contributes to a rapidly growing appreciation of neuroimmune crosstalk in chronic disease. The idea that nerves do more than transmit sensation and regulate tone, that they actively sculpt local immune responses through neuropeptide release, has gained traction in fields ranging from intestinal inflammation to tumor immunology. This work extends that framework to the liver, an organ densely innervated at portal triads and richly supplied by sympathetic fibers, and identifies a concrete molecular itinerary by which neural input becomes fibrotic output. It raises provocative questions about whether chronic stress, which elevates sympathetic outflow and systemic NPY, might modulate fibrosis progression in patients, a hypothesis the current study does not directly test but which its findings make testable.

Caveats remain, as they do in any preclinical study. The mouse models, carbon tetrachloride injury and DDC diet, are established but imperfect proxies for the heterogeneous fibrotic diseases seen in clinics, and the human tissue analysis, while consistent with the animal data, is observational. Whether NPY receptor blockade can safely slow or reverse established fibrosis in patients will require medicinal chemistry, pharmacokinetics, and eventually clinical trials that this paper does not provide. Still, by connecting sympathetic nerves, macrophage polarization, PI3K-MAPK signaling, and stellate cell activation into a single coherent pathway, the Xi’an team has converted a diffuse suspicion that the nervous system matters in liver disease into a specific, targetable hypothesis. For the millions of people living with chronic liver disease worldwide, that specificity is precisely what the field needs.

Subject of Research: Neuroimmune signaling by neuropeptide Y in macrophage polarization and hepatic fibrosis

Article Title: NPY promotes macrophage polarization and hepatic fibrogenesis via PI3K/MAPK-dependent neuroimmune mechanisms

Article References: Lin, Q., Zheng, X., Dou, W., Bai, Q., Liang, S., Kou, Z., Guo, H., Ding, Y., Zhao, S., Wang, J., Yin, J., & Liu, Z. (2026). NPY promotes macrophage polarization and hepatic fibrogenesis via PI3K/MAPK-dependent neuroimmune mechanisms. Cellular and Molecular Life Sciences, 83(1), Article 346. https://doi.org/10.1007/s00018-026-06428-2

Image Credits: AI Generated

DOI: 10.1007/s00018-026-06428-2

Keywords: neuropeptide Y, hepatic fibrosis, macrophage polarization, NPY1R, NPY2R, PI3K signaling, MAPK, sympathetic nervous system, hepatic stellate cells, liver cirrhosis, neuroimmune crosstalk, cytokines