VIP

Neuronal VIP shapes intestinal stem cell activity and mucosal immunity.

Camilla Anastasio, Lucie Peduto

Intestinal homeostasis and regeneration rely on intestinal stem cells (ISCs). Li et al.1 identified neuronal vasoactive intestinal peptide (VIP) as a brake on ISCs through VIPR1 to limit regeneration. In Nature Immunology, Jakob et al. and Pirzgalska et al. further showed that VIP-VIPR1 signaling restrains secretory lineage expansion and balances immune responses.2,3.

Neurogenic Inflammation and Immune Dysregulation in Psoriasis: Mechanistic Pathways and Emerging Interventions.

Hemraj Singh, Rajeev Taliyan

Psoriasis is a chronic, immune-mediated inflammatory disorder characterized by keratinocyte hyperproliferation and systemic immune dysregulation. The neuroimmune axis, linking sensory nerve activity, neuropeptide signaling, and immune responses, is central to disease pathogenesis. Structural remodeling of sensory nerves enhances the release of neuropeptides such as Substance P, calcitonin gene-related peptide, vasoactive intestinal peptide, and neuropeptide Y, which activate dendritic cells, promote T-cell proliferation, and stimulate keratinocyte cytokine production, sustaining a neurogenic inflammatory loop. Psychological stress exacerbates inflammation through hypothalamic-pituitary-adrenal (HPA) axis dysregulation, altering cortisol signaling and systemic immune responses. Intracellular pathways, including mitogen-activated protein kinase, PI3KAktmTOR, JAKSTAT, and NF-κB, along with epigenetic modifications, integrate neural and immune signals, contributing to disease chronicity and heterogeneity. Targeting neuroimmune interactions through neuropeptide antagonists, neuromodulation, stress management, and precision immunotherapies reduces cutaneous inflammation and addresses systemic comorbidities. This review synthesizes molecular, cellular, and clinical insights into the neuroimmune-HPA axis network in psoriasis, highlighting its therapeutic potential for personalized and multidisciplinary management.

Ameliorative effects of Atractylodes macrocephala insoluble dietary fiber on loperamide-induced functional constipation in rats.

Senye Wang, Wenjing Feng, Suxing Tu +5 more

In this study, loperamide hydrochloride (LOP) was used to establish a rat model of functional constipation (FC) to explore the mechanism of Atractylodes macrocephala insoluble dietary fiber (AMDF) in improving FC. The results showed that AMDF could increase the fecal water content and small intestinal advancement rate of FC rats, raise the levels of gastrin (GAS), vasoactive intestinal peptide (VIP), and substance P (SP) in serum, reduce the level of somatostatin (SS), reduce the levels of IL-6, TNF-α, and NO in serum, and alleviate the pathological state of colon tissue. The 16S rDNA sequencing results revealed that AMDF could enhance the diversity of the intestinal microbiota and restore the ratio of Firmicutes/Bacteroides (F/B). Metabolomics results show that AMDF treatment can regulate bile secretion, primary bile acid biosynthesis, amino acid metabolic signaling pathways, etc. Meanwhile, AMDF could inhibit the activation of the NF-κB signaling pathway in colon tissue and alleviate intestinal inflammation in FC rats. In conclusion, the research results showed that AMDF can improve the intestinal microbiota and metabolism, and inhibit the intestinal inflammatory response, achieving the effect of relieving FC.

Food-specific IgG-based elimination diet decreased IL-6, TNF-α, and CGRP and improved symptoms in adults with migraine.

Zhiming Zhao, Meimei Yang, Fujun Wan +4 more

Food-specific IgG antibodies have been proposed to be biomarkers to identify food that triggers an inflammation response. We aimed to evaluate the effect of a food-specific IgG-based elimination diet by assessing the changes in the symptoms of migraine and its comorbidities, inflammatory cytokines, neuropeptides, and neurotransmitters, and their correlation.

The Neuropsychological Dimensions to Pathogenesis of Chronic Spontaneous Urticaria Beyond Autoallergy - A Brief Narrative Review.

M Sendhil Kumaran, Sahibpreet Kaur, Davinder Parsad +1 more

Chronic spontaneous urticaria (CSU) is a burdensome dermatological condition with a complex, multifactorial pathogenesis involving intricate immune, neurological, and psychological interactions. While traditional models primarily emphasize auto-allergic mechanisms, evidence highlights the critical role of neuroimmune interaction in the chronicity and exacerbation of disease. This review examines the neuroimmune contributions to CSU pathogenesis, focusing on mast cell (MC)-sensory neuron interactions, autonomic nervous system dysregulation, neuroinflammatory pathways, and psychological comorbidities that perpetuate disease activity. A comprehensive narrative review of the literature was undertaken, evaluating mechanisms such as MC activation through immunoglobulin-E (IgE)-independent pathways, neuropeptide-mediated inflammation, hypothalamic-pituitary-adrenal (HPA) axis dysregulation, and psychiatric associations with CSU. Findings indicate that beyond the classical IgE-mediated MC degranulation, neurogenic inflammation via Mas-Related G-Protein Coupled Receptor X2 (MRGPRX2) receptors-triggered by neuropeptides such as substance P and vasoactive intestinal peptide-plays a pivotal role. Chronic psychological stress activates the HPA axis, contributing to MC hyperactivity and reinforcing the pruritus-stress cycle. Furthermore, a high prevalence of psychiatric comorbidities, including anxiety and depression, contributes to central sensitization and worsens disease severity. The interplay of T cells, basophils, eosinophils, and endothelial cells further amplifies the neuroimmune-inflammatory network. These insights suggest that optimal CSU management requires an integrated approach encompassing dermatological, immunological, and psychological interventions. Emerging therapies targeting neuroimmune pathways, such as MRGPRX2 antagonists, beta-adrenergic blockers, and cognitive-behavioral strategies, show promise. Future research should prioritize the development of personalized neuroimmune-directed therapies to enhance disease control in CSU.

Neuroimmune Crosstalk in Psoriasis: Mechanisms and Therapeutic Implications.

Hanlin Gao, Yi Fang, Yue Zhang +3 more

Psoriasis is a chronic, immune-mediated inflammatory skin disorder characterized by keratinocyte hyperproliferation, dermal vascular remodeling, and dense immune cell infiltration. While the conventional immunopathological model emphasizes the IL-23/Th17 axis and aberrant T-cell responses, growing evidence highlights the central role of neuroimmune crosstalk in the initiation, amplification, and persistence of disease. This review systematically dissects the cellular and molecular mechanisms underpinning neuroimmune interactions in psoriasis, focusing on the dynamic interplay between peripheral nerve fibers, keratinocytes, and immune cells. Key neuropeptides—such as calcitonin gene-related peptide (CGRP), substance P (SP), nerve growth factor (NGF), and vasoactive intestinal peptide (VIP)/PACAP—emerge as critical mediators that activate proinflammatory signaling cascades and perpetuate a positive feedback loop involving IL-23, IL-17, and other cytokines. Concurrently, neurotransmitters including norepinephrine (NE), acetylcholine (ACh), and dopamine (DA) modulate dendritic cell activation, Th17 polarization, and epidermal inflammation via adrenergic, cholinergic, and dopaminergic pathways. Importantly, both central and peripheral nervous systems are implicated in neuroinflammatory sensitization, with IL-17 A, IL-1β, and TNF-α disrupting neuronal homeostasis and contributing to pruritus, pain, and stress-induced relapse. We further summarize emerging therapeutic strategies targeting the neuroimmune axis—such as TRPV1 antagonists, botulinum neurotoxins, NK1R inhibitors, and vagus nerve stimulation—which offer promising avenues for personalized and mechanism-based interventions. By reframing psoriasis as a neuroimmune disorder, this review provides new conceptual insights into disease heterogeneity and points toward innovative treatment paradigms.

Aviptadil Therapy in Acute Respiratory Distress Syndrome Patients: A Systematic Review and Meta-analysis.

Ashritha A Udupa, Pratibha Todur, Souvik Chaudhuri +8 more

Acute respiratory distress syndrome (ARDS) is a life-threatening condition with a high mortality rate despite advances in supportive care. Aviptadil, a synthetic analogue of vasoactive intestinal peptide (VIP), exhibits anti-inflammatory potential and cytoprotective effects that may improve pulmonary function. However, its role in improving survival among ARDS patients remains uncertain. This systematic review and meta-analysis aimed to evaluate the effectiveness of aviptadil in improving survival and oxygenation outcomes in ARDS.

The neuro-cutaneous axis: the role of nerve cells in wound healing.

Yijing Zhou, Jin Yang, Lin Chen +2 more

This narrative review summarizes the primary regulatory function of the neurocutaneous axis in wound healing. Hemostasis, inflammation, proliferation, and remodeling are the four phases of skin wound healing. Neurons release neuropeptides like substance P (SP), calcitonin gene-related peptide (CGRP), and vasoactive intestinal peptide (VIP) along with neurotrophic factors. They initiate vasodilation and promote platelet aggregation during the hemostasis phase, regulate immune cell recruitment and activity during the inflammatory phase, promote keratinocyte migration, fibroblast activation, and angiogenesis during the proliferation phase, and participate in the ordered arrangement of collagen and neural reinnervation during the remodeling phase. Furthermore, the clearance of apoptotic cells by macrophage-mediated phagocytosis couples the resolution of inflammation with the onset of regeneration, forming a closed-loop mechanism through signal contact between the neuro-immune-skin cell network. Along with offering theoretical references for wound regeneration, this paper also examines focused therapeutic approaches such as neuropeptide delivery, the synergistic use of conductive materials and electrical stimulation, and stem cell and gene therapy.

Can diets alleviate constipation and promote bowel movement? Exploring the underlying mechanisms of effects.

Xi Gui, Lan Wu, Kaijun Huang +7 more

Constipation is a common gastrointestinal disorder with a significant impact on quality of life. Diets play an important role as a modifiable lifestyle factor that can affect the onset and progression of constipation. This review examines the effects and mechanisms of multiple dietary patterns, including a high-fat diet, Mediterranean diet, fiber-rich diet, and plant-based diet, on constipation, microecological agents (probiotics, prebiotics, and synbiotics), and bioactive compounds (polysaccharides and polyphenols). In summary, the Mediterranean and plant-based diets can reduce the risk of constipation with favorable changes in gut microbiota, increase contents of short-chain fatty acids (SCFAs), and reduce the inflammatory markers. A fiber-rich diet increases stool bulk, retains water due to its high water-binding capacity, and serves as a substrate for gut microbiota. Additionally, microbiota can ferment fiber-rich diet to produce gases and SCFAs, which create an osmotic load and accelerate intestinal transit. Conversely, a high-fat diet correlates with an increased incidence of constipation with unfavorable changes in gut microbiota and reduces 5-hydroxytryptamine (5-HT) availability and mucin secretion. Meanwhile, probiotics, prebiotics, and synbiotics relieve constipation by restoring the imbalance of gut microbiota and increasing the contents of SCFAs and neurotransmitters. Also, polyphenols alleviate constipation by enhancing intestinal barrier, balancing neurotransmitters, and suppressing gut inflammation. Polysaccharides upregulate the expression of gastrointestinal transport proteins and genes (such as transient receptor potential vanilloid 1 [TRPV1], aquaporin 3 [AQP3], vasoactive intestinal peptide receptor 1 [VIPR1]) to maintain intestinal peristalsis. Furthermore, given the inter-individual in metabolic responses to dietary intake, we propose a framework for developing personalized diets for individuals with constipation, tailored to their specific compositions of gut microbiota.

Mechanisms of acupuncture in the treatment of dry eye disease: narrative review of experimental studies.

Yuanchao Fu, Chengzhi Liu, Guzhi Xu

Dry Eye Disease (DED) is a common ocular disorder characterized by tear film instability, ocular inflammation, and discomfort, which significantly affects the quality of life. Traditional treatments primarily address the symptoms but do not always target the underlying pathophysiology of DED. Acupuncture, a complementary therapy in traditional Chinese medicine, has shown the potential to improve DED symptoms through multiple mechanisms. This review aimed to explore the therapeutic effects of acupuncture on DED, focusing on its role in enhancing lacrimal gland function, modulating inflammatory pathways, and alleviating ocular pain.

Electroacupuncture alleviates intestinal ischemia-reperfusion-induced acute lung injury via the vagus-sympathetic nerve pathway.

Shihua Lv, Can Ma, Wenchao Fu +6 more

Intestinal ischemia-reperfusion (II/R) injury predominantly causes acute lung injury (ALI), and in severe instances, acute respiratory distress syndrome, both associated with high mortality. Electroacupuncture (EA) excels in regulating autonomic nervous system balance and safeguarding organ function. This study delved into EA's impacts and mechanisms on II/R-induced ALI.

Nociceptor neurons suppress alveolar macrophage-induced Siglec-F+ neutrophil-mediated inflammation to protect against pulmonary fibrosis.

Carlos H Hiroki, Mortaza F Hassanabad, Manon Defaye +22 more

Pulmonary fibrosis results from persistent and pathological tissue repair, which is therapeutically challenging to attenuate and often fatal. The immune processes involved in fibrosis remain ill defined. Using a bleomycin-induced lung fibrosis murine model, we discovered that vagal TRPV1+ nociceptors are protective. Pharmacological ablation or genetic deletion of nociceptors resulted in worsened fibrosis and outcomes. Without nociceptors, alveolar macrophages aberrantly produced vasoactive intestinal peptide (VIP), leading to cytokine TGF-β1-mediated alternative proinflammatory Siglec-F+ neutrophil recruitment to the lung with a high propensity for neutrophil extracellular trap (NET) formation. VIP inhibition or Vip deletion in hematopoietic cells improved outcomes and attenuated Siglec-F+ neutrophil recruitment to the lungs in nociceptor-deficient mice, while VIP administration had the opposite effect. Thus, nociceptors are essential regulators of inflammation during pulmonary fibrosis. These findings provide mechanistic insights into how the nervous system impacts the progression of fibrotic lung diseases.

Unmasking the intestinal impact: Acute Toxoplasma gondii infection induces severe morphological and immunological changes in female C57BL/6 mice.

Paulo Watanabe, Vivian Fuguhara de Lima, Amanda Gubert Alves Dos Santos +6 more

Toxoplasmosis, caused by the protozoan Toxoplasma gondii (T. gondii), is a common zoonotic disease with a seropositivity rate of up to 60 % in adults. While often asymptomatic, it can cause severe complications in immunocompromised individuals. Oral transmission is the primary route of infection, leading to intestinal inflammation. This study evaluated morphoquantitative changes in the colons of female C57BL/6 mice acutely infected with T. gondii. Mice were divided into control and infected groups and euthanized five days post-infection for colon collection. Histological analyses quantified intraepithelial lymphocytes, goblet cells, mast cells, and collagen fibres, while immunostaining assessed neurons and vasoactive intestinal peptide (VIP) expression. Infected mice exhibited increased intraepithelial lymphocytes and myeloperoxidase activity, alongside a significant reduction in AB-1.0-positive goblet cells, indicating impaired mucus secretion. Notably, the longitudinal muscle layer showed increased thickness, whereas the submucosal layer and crypt depth were reduced. Histopathological evaluation revealed epithelial hyperplasia, mucosal ulceration, and abscess formation. A decrease in myenteric neurons was also observed, although VIP expression remained unchanged. These findings demonstrate that acute T. gondii infection induces substantial alterations in intestinal structure, including immune cell infiltration, goblet cell depletion, and muscle layer remodelling. The reduction in myenteric neurons, despite stable VIP expression, suggests specific neuroimmune interactions in the infected gut. Collectively, this study highlights the profound impact of T. gondii on colonic morphology and function, underscoring the complexity of host-parasite interactions during acute infection.

Oat Fiber Alleviates Loperamide-Induced Constipation in Mice by Modulating Intestinal Barrier Function.

Yufei Shi, Yuchao Han, Jie Jiang +8 more

Objective: To investigate the effects of oat fiber on animal constipation and elucidate its underlying mechanisms. Methods: Male BALB/c mice were randomly allocated into five groups: control group (CON), model control group (MODEL), low dose group (LOW), middle dose group (MIDDLE), high dose group (HIGH). Constipation was induced in the mice by intragastric administration of loperamide. Subsequently, the mice (except those in the CON and MODEL groups) were administered oat fiber intragastrically for 21 consecutive days. Results: Compared with the MODEL group, oat fiber significantly increased the number of fecal pellets, fecal wet weight, and fecal water content (p < 0.05), shortened the time to first black stool excretion (p < 0.05), and enhanced the small intestinal propulsion rate in constipated mice. Additionally, oat fiber significantly upregulated motilin (MTL) and gastrin (GAS) levels (p < 0.05), while downregulating vasoactive intestinal peptide (VIP) and somatostatin (SS) levels (p < 0.05). It also significantly reduced the transcription level of Aquaporin 8 (AQP8) (p < 0.05), effectively alleviating intestinal mucosal injury and immune inflammation. The relative expression levels of TNF-α and IL-1β were significantly decreased in the oat fiber group (p < 0.05). Gut microbiota analysis revealed that oat fiber increased both the abundance and diversity of gut microbiota in constipated mice. Specifically, oat fiber was found to enhance the relative abundance of Firmicutes while reducing that of Bacteroidetes. At the genus level, it promoted the proliferation of Lachnospiraceae_NK4A136_group and Roseburia. Conclusions: Oat fiber alleviates constipation in mice by modulating gastrointestinal regulatory peptides, gut microbiota, aquaporin and mitigating intestinal barrier damage and immune-inflammatory responses.

Plasma levels of biomarkers associated with vasodilation and neuroinflammation in pediatric patients with head trauma and their relationship with clinical characteristics of patients.

Yasemin Baranoglu Kilinc, Yasar Dagistan, Erkan Kilinc

Traumatic brain injury in children can lead to lifelong sequelae and disabilities. Identifying the mediators of the neuroinflammatory process resulting from head trauma is of great importance. We therefore explored the plasma levels of neurogenic inflammatory and vasodilator peptides in children with head trauma and their relationship with the clinical characteristics of the patients.

2'-Fucosyllactose synbiotics with Bifidobacterium bifidum to improve intestinal transcriptional function and gut microbiota in constipated mice.

Yi Shan, Miaomiao Zheng, Weiwei Liang +2 more

Probiotics, prebiotics, and synbiotics are potential therapeutic options for constipation. However, the synergistic effects and underlying mechanisms of 2'-fucosyllactose (2'-FL) and Bifidobacterium bifidum (B. bifidum) in ameliorating constipation remain unclear. In this study, constipated mice were treated 2'-FL combined with B. bifidum, and their effects were evaluated based on defecation performance, gastrointestinal regulatory peptide levels, intestinal inflammation, and barrier function. Transcriptomics and 16S rRNA sequencing were performed to assess gene expression and gut microbiota composition, respectively. The results demonstrated that 2'-FL + B. bifidum enhanced intestinal secretion of gastrin and substance P while suppressed vasoactive intestinal peptide, improving defecation parameters. Furthermore, 2'-FL + B. bifidum significantly reduced the levels of tumor necrosis factor-α (TNF-α), interleukin (IL)-1β, and IL-6 while increasing IL-10 levels. It also upregulated intestinal tight junction proteins (ZO-1, Claudin-1, and Occludin) and reduced serum markers of intestinal permeability (D-lactic acid, enterotoxin, and diamine oxidase). Transcriptomic analysis revealed that 2'-FL + B. bifidum upregulated genes related to the immune system processes, signaling pathways, ABC transporters, glycolysis/gluconeogenesis, and butanoate metabolism. Furthermore, our results demonstrated that 2'-FL + B. bifidum could regulate the composition of the gut microbiota in constipated mice, promoting the growth of beneficial intestinal bacteria, such as Akkermansia, Bifidobacterium, and Parabacteroides. In summary, 2'-FL + B. bifidum alleviates constipation in mice by regulating intestinal transcriptional profiles and the gut microbiota composition. This study provides theoretical support for the development and application of synbiotics containing 2'-FL and B. bifidum.

Comparative Analysis of CGRP, VIP and 
PACAP-38 Levels in Migraine with and 
Without Aura: A Case-control Study.

N Sreevani, B Ramesh, K Maheshkumar +1 more

Migraine pathophysiology involves the release of vasoactive neuropeptides following trigeminovascular system activation. While calcitonin gene-related peptide (CGRP), vasoactive intestinal peptide (VIP) and pituitary adenylate cyclase-activating polypeptide-38 (PACAP-38) have been individually studied in migraine, their combined role in differentiating migraine subtypes remains unclear.

Gut neuropeptide involvement in Parkinson's disease.

Hayley N Templeton, Stuart A Tobet, Luke A Schwerdtfeger

Parkinson's disease (PD) is a neurodegenerative disorder affecting over 10 million people. A key pathological feature of PD is the accumulation of misfolded α-synuclein (aSyn) protein in the substantia nigra pars compacta. Aggregation of aSyn can form Lewy bodies that contribute to dopaminergic neuron degeneration and motor symptoms, such as tremor, rigidity, and bradykinesia. Beyond the central nervous system, aSyn aggregates have been detected in the gastrointestinal (GI) tract, suggesting a link between peripheral aSyn and nonmotor PD symptoms. GI symptoms, often preceding motor symptoms by up to 20 years, highlight the bidirectional communication between the central nervous system and the enteric nervous system (gut-brain axis) in PD. Although microbiome alterations and intestinal inflammation have been associated with PD, functional impacts on gut-brain signaling or aSyn aggregation remain unclear. Intestinal neuropeptides are key modulators of gut-brain communication, alter immune response to pathogens and environmental toxins, and may contribute to the function of the luminal gut barrier. Dysregulation of gut neuropeptide signaling, including vasoactive intestinal peptide, neuropeptide Y, calcitonin gene-related peptide, ghrelin, cholecystokinin, glucagon-like peptide 1, and substance P, have been associated with pathologic effects of PD in animal models. Despite their potential role in pathogenesis and disease modulation, gut neuropeptide roles in PD are underexplored. This article reviews current knowledge surrounding microbial metabolite and immune influences on gut neuropeptide signaling, aSyn aggregation in the enteric nervous system, and downstream neuroimmune pathway alterations within the context of PD and its mouse models.

Vasoactive Intestinal Peptide (VIP) in COVID-19 Therapy-Shedding of ACE2 and TMPRSS2 via ADAM10.

Charlotte Gutzler, Kerstin Höhne, Daniele Bani +9 more

Patients infected with SARS-CoV-2 may develop mild respiratory symptoms but also Acute Respiratory Distress Syndrome (ARDS). Additionally, severe systemic inflammation contributes to morbidity and mortality. The SARS-CoV-2 virus enters the cell by binding to the angiotensin-converting enzyme 2 (ACE2) receptor, followed by cleavage by transmembrane serine protease 2 (TMPRSS2). Vasoactive intestinal peptide (VIP) is known for its immune-modulating effects by suppressing the release of pro-inflammatory cytokines and enhancing regulatory T-cells. Furthermore, it has been tested in SARS-CoV-2-related clinical trials. We set out to investigate its role in the setting of SARS-CoV-2 infection in vitro. Epithelial cells (CaCo-2) were stimulated with SARS-CoV-2 spike protein, treated with native VIP and analyzed to investigate the mRNA and surface expression of ACE2 and TMPRSS2, the enzyme activity of TMPRSS2 and the infection rate by a SARS-CoV-2 pseudovirus. VIP downregulated ACE2 and TMPRSS2 mRNA and surface expression. Beyond these direct effects, VIP mediates the shedding of surface-expressed ACE2 and TMPRSS2 via upregulation of a sheddase protease (ADAM10). Functionally, these dual mechanisms of VIP-mediated downregulation of proteins involved in SARS-CoV-2 cell entry resulted in a reduced infection rate by the SARS-CoV-2 pseudovirus. These data imply that VIP hampers viral entry mechanisms based on SARS-CoV-2 and the linkage to ADAM10 may stimulate research in other indications beyond SARS-CoV-2.

Vasoactive Intestinal Peptide: A Neuropeptide that Plays an Important Role in Parkinson's Disease.

Wenhui Fan, Ke Li, Ruohua Wang +5 more

Parkinson's disease (PD) is primarily characterized by rigidity and tremor, which are pathologically associated with α -synuclein aggregation, especially in dopaminergic neurons in the midbrain. As it is a multi-factorial disease, there are currently no effective treatments but only mitigative therapies. Vasoactive intestinal peptide (VIP), a 28-amino acid neurotransmitter, is widely distributed in both the central and peripheral nervous system with a broad biological effect. Studies have shown that VIP exhibits anti-inflammatory, antioxidant, and anti-apoptotic effects and regulates glial cells and immune cells to protect and repair nerve cells. This article reviews the research progress of VIP as a brain-gut peptide in the treatment of PD and possible future research directions.

Neuroimmune mechanisms of type 2 inflammation in the skin and lung.

Masato Tamari, Aaron M Ver Heul

Type 2 inflammation has a major role in barrier tissues such as the skin and airways and underlies common conditions including atopic dermatitis (AD) and asthma. Cytokines including interleukin 4 (IL-4), IL-5, and IL-13 are key immune signatures of type 2 inflammation and are the targets of multiple specific therapeutics for allergic diseases. Despite shared core immune mechanisms, the distinct structures and functions of the skin and airways lead to unique therapeutic responses. It is increasingly recognized that the nervous system has a major role in sensing and directing inflammatory processes. Indeed, crosstalk between type 2 immune activation and somatosensory functions mediates tissue-specific signatures such as itching in the skin. However, neuroimmune interactions are shaped by distinct neuronal and immune landscapes, and differ between the skin and airways. In the skin, dorsal root ganglia-derived neurons mediate pruritus via type 2 cytokines and neurogenic inflammation by mast cell or basophil activation. Conversely, vagal ganglia-derived neurons regulate airway immune responses by releasing neuropeptides/neurotransmitters such as calcitonin gene-related peptides, neuromedin U, acetylcholine, and noradrenaline. Sensory neuron-derived vasoactive intestinal peptide forms a feedback loop with IL-5, amplifying eosinophilic inflammation in the airways, a mechanism that is absent in the skin. These differences influence the efficacy of cytokine-targeted therapies. For instance, IL-4/IL-13-targeted therapies like dupilumab demonstrate efficacy in AD and allergic airway diseases, whereas IL-5-targeted therapies are effective in eosinophilic asthma but not AD. Understanding these neuroimmune interactions underscores the need for tailored therapeutic approaches to address allergic diseases where barrier tissues are involved.

Proinflammatory cytokines and neuropeptides in psoriasis, depression, and anxiety.

Emily L Keenan, Richard D Granstein

Psoriasis vulgaris has established associations with psychiatric conditions such as depression, anxiety, and chronic stress. This review aims to evaluate current theories and evidence regarding the role of proinflammatory cytokines and neuropeptides in connecting systemic inflammation, psychological stress, and inflammatory skin diseases, namely psoriasis. A literature review was conducted to analyze studies that explore the connections between psoriasis, psychiatric conditions, and biological mediators, including inflammatory cytokines [interferon (IFN)-γ, interleukin (IL)-1, IL-2, IL-6, IL-12, tumor necrosis factor (TNF)-α, IL-22, IL-17], neuropeptides [calcitonin gene-related peptide (CGRP), substance P (SP), and vasoactive intestinal peptide (VIP)], as well as the hypothalamic-pituitary-adrenal (HPA) axis. Existing literature indicates that psychiatric state can influence cutaneous conditions through immune, neural, and endocrine mediators. The elevated rates of anxiety and depression observed in psoriasis patients are likely due to both the inflammatory process itself and the chronic stress associated with disease management, highlighting the importance of managing stress, and addressing mental health to improve clinical outcomes. While the literature suggests proinflammatory cytokines and neuropeptides may be key links between systemic inflammation, psoriasis, and psychiatric comorbidities, further research is necessary to continue to elucidate physiological mechanisms and explore the potential for new treatment modalities.

Ovarian premature aging: VIP as key regulator of fibro-inflammation and foamy macrophages generation.

Lara Castagnola, Lucila Gallino, Ana Schafir +8 more

Ovarian aging is associated with fibro-inflammation, contributing to the decline in oocyte count and quality. Given the immunomodulatory properties of the vasoactive intestinal peptide (VIP) in the reproductive tract, we investigated its role in maintaining ovarian immune homeostasis and preventing premature aging. We evaluated young VIP knockout (KO) mice, comparing them to young wild type (WT) females, for signs of premature aging. Histological staining revealed aberrant ovarian morphology in VIP KO mice, characterized by increased atretic follicles and decreased ovarian reserve compared to WT controls. Moreover, VIP KO ovaries showed reduced vascularization, increased collagen deposition and elevated ROS and IL-1β levels. Foamy macrophages were significantly predominant, indicating premature aging in young VIP KO ovaries. To determine potential mechanisms behind these pathogenic changes, we conditioned peritoneal macrophages from young WT or VIP KO mice in vitro with ovarian-conditioned media from young WT or VIP KO mice to mimic the respective ovarian microenvironment. When WT or VIP KO peritoneal macrophages were conditioned with ovarian media from their respective genotypes, lipid droplet accumulation increased compared to control medium. In cross-genotype experiments, WT macrophages conditioned with media from VIP KO ovaries selectively accumulated higher levels of lipid droplets, whereas no differences were observed in VIP KO macrophages conditioned with WT ovarian media. This suggests that VIP KO macrophages are uniquely sensitized to the inflammatory environment of VIP KO ovaries, implicating both ovarian factors and macrophage status. These findings highlight the role of VIP in preventing fibro-inflammation, thereby preserving ovarian health and preventing premature aging.

TNBS colitis induces architectural changes and alpha-synuclein overexpression in mouse distal colon: A morphological study.

Arianna Casini, Giorgio Vivacqua, Ludovica Ceci +16 more

Alpha-synuclein (α-syn) is widely expressed in presynaptic neuron terminals, and its structural alterations play an important role in the pathogenesis of Parkinson's disease (PD). Aggregated α-syn has been found in brain, in the peripheral nerves of the enteric nervous system (ENS) and in the intestinal neuroendocrine cells during synucleinopathies and inflammatory bowel disorders. In the present study, we evaluated the histomorphological features of murine colon with 2,4,6-trinitrobenzene sulfonic acid (TNBS)-induced colitis, a common model of colitis. Thereafter, we investigated the expression of α-syn, Toll-like receptor 4 (TLR4), choline acetyltransferase (ChAT), vasoactive intestinal peptide (VIP), tyrosine hydroxylase (TH), calcitonin gene-related peptide (CGRP), and calcitonin-like receptor (CALCR). Finally, we investigated the presence of phosphorylated α-syn (pS129 α-syn) aggregates and their relationship with inflammatory cells. Colon from TNBS mice showed an increase in inflammatory cells infiltrate and significative changes in the architecture of the intestinal mucosa. α-Syn expression was significantly higher in inflamed colon. VIP was increased in both the mucosa and muscularis externa of TNBS mice, while TH, CGRP, and CALCR were significantly reduced in TNBS mice. Amyloid aggregates of pS129 α-syn were detectable in the ENS, as in the macrophages around the glands of the mucosa correlating with the markers of inflammation. This study describes - for the first time - the altered expression of α-syn and the occurrence of amyloid α-syn aggregates in the inflammatory cells under colitis, supporting the critical role of bowel inflammation in synucleinopathies and the involvement of α-syn in IBD.

Unraveling the relationship between inflammation and cluster headache.

Yu-Wen Wang, Xu-Hong Yang, Xin-Hui Zheng +4 more

Cluster headache (CH) is often referred to as the 'suicide headache.' Existing research suggests that the activation of the trigeminal-vascular system, increased sensitivity of nerve fibers, and the release and interaction of various neuropeptides and inflammatory mediators may contribute to neurogenic inflammation, which serves as a crucial pathophysiological basis for the development of CH. Additionally, some neuropeptides can modulate neuronal activity related to pain transmission and may increase pain perception by sensitizing central nerves. This review discusses the neuropeptides and inflammatory mediators associated with CH neuroinflammation, focusing on calcitonin gene-related peptide (CGRP), inflammatory cytokines and related signaling pathways, nitric oxide (NO), pituitary adenylate cyclase-activating peptide 38 (PACAP-38), and vasoactive intestinal peptide (VIP), incorporating both preclinical and clinical evidence to provide new insights into potential therapeutic targets for CH.

Antimicrobial neuropeptides and their therapeutic potential in vertebrate brain infectious disease.

Xiaoke Li, Kaiqi Chen, Ruonan Liu +2 more

The defense mechanisms of the vertebrate brain against infections are at the forefront of immunological studies. Unlike other body parts, the brain not only fends off pathogenic infections but also minimizes the risk of self-damage from immune cell induced inflammation. Some neuropeptides produced by either nerve or immune cells share remarkable similarities with antimicrobial peptides (AMPs) in terms of size, structure, amino acid composition, amphiphilicity, and net cationic charge. These similarities extend to a wide range of antibacterial activities demonstrated in vitro, effectively protecting nerve tissue from microbial threats. This review systematically examines 12 neuropeptides, pituitary adenylate cyclase-activating peptide (PACAP), vasoactive intestinal peptide (VIP), α-melanocyte stimulating hormone (α-MSH), orexin-B (ORXB), ghrelin, substance P (SP), adrenomedullin (AM), calcitonin-gene related peptide (CGRP), urocortin-II (UCN II), neuropeptide Y (NPY), NDA-1, and catestatin (CST), identified for their antimicrobial properties, summarizing their structural features, antimicrobial effectiveness, and action mechanisms. Importantly, the majority of these antimicrobial neuropeptides (9 out of 12) also possess significant anti-inflammatory properties, potentially playing a key role in preserving immune tolerance in various disorders. However, the connection between this anti-inflammatory property and the brain's infection defense strategy has rarely been explored. Our review suggests that the combined antimicrobial and anti-inflammatory actions of neuropeptides could be integral to the brain's defense strategy against pathogens, marking an exciting direction for future research.

The mechanism of transcutaneous gastric pacing treatment on gastrointestinal motility recovery and inflammation improvement in early-stage acute pancreatitis patients.

Zhenyu Jia, Lingchao Kong, Xiaochun Lu +4 more

Acute pancreatitis (AP) is often accompanied by gastrointestinal motility disorders. The purpose of this study was to investigate the efficacy and possible mechanism of transcutaneous gastric pacing (TGP) in early-stage AP patients.

Microplastic and the Enteric Nervous System: Effect of PET Microparticles on Selected Neurotransmitters and Cytokines in the Porcine Ileum.

Ismena Gałęcka, Jarosław Całka

Microplastic is an environmental hazard to which both animals and humans are exposed. Current reports show that it can cause inflammation, including in the gastrointestinal tract. To examine the impact on the ileum, 15 eight-week-old gilts (five individuals/group) were exposed to PET microplastics (7.6 µm-416.9 µm) at a dose of 0.1 g/day or 1 g/day for 28 days. The collected ileum fragments were investigated for the cytokine concentrations (IL-1β, IL-6, IL-8, IL-10, and TNF-α; ELISA test), neuron populations (cocaine and amphetamine-regulated transcript, galanin, neuronal nitric oxide synthase, substance P, vesicular acetylcholine transporter, and vasoactive intestinal peptide; immunofluorescence staining), and morphometric parameters (histological analysis). Under the influence of MP-PET, there was a reduction in the populations of CART- and GAL-positive neurons in the submucosal plexuses and of nNOS-, VAChT-, and VIP-positive neurons in all the plexuses. In contrast, there was an increase in GAL-positive neurons in the myenteric plexus and SP-positive neurons in all the plexuses. The concentrations of IL-1β, IL-6, IL-8, IL-10, and TNF-α did not undergo statistically significant changes under the influence of the low or high dose of MP-PET. The changes in the histological structure exclusively concerned the thinning of the mucosa and the muscularis externa. The results support the thesis that MP-PET is not neutral to the ileal cells.

Lacticaseibacillus paracasei NCU-04 relieves constipation and the depressive-like behaviors induced by loperamide in mice through the microbiome-gut-brain axis.

Shengjie Li, Yi Li, Yujie Cai +5 more

Constipation is a prevalent gastrointestinal condition that significantly affects patients' physical and mental well-being, yet current treatments often lack safety and efficacy. Emerging evidence highlights the critical role of the microbiota-gut-brain axis (MBGA) in managing constipation, paving the way for probiotics as an adjuvant treatment to improve constipation symptoms. In this study, we isolated a gut probiotic strain, Lacticaseibacillus paracasei NCU-04, and investigated its improvement effects on loperamide-induced constipation in mice. We demonstrated that L. paracasei NCU-04 exhibited excellent probiotic properties, including robust growth, strong antibacterial and antioxidant capacities, and a lack of hemolytic activity in vitro. The administration of L. paracasei NCU-04 effectively improved the defecation-related indicators such as the fecal water content, time to the first black stool defecation, and intestine transit rate, suggesting enhanced gut immobility in constipated mice. Additionally, L. paracasei NCU-04 significantly reduced colon inflammation induced by loperamide. Further, L. paracasei NCU-04 increased levels of colonic motilin, 5-hydroxytryptamine (5-HT), and c-kit, while decreased that of aquaporin 3, vasoactive intestinal peptide, and peptide YY. Notably, L. paracasei NCU-04 effectively upregulated the expression of 5-HT and its receptor (i.e., 5-HT4R) in the brains of constipated mice. High-throughput sequencing revealed that L. paracasei NCU-04 restored the diversity and composition of the gut microbiota disturbed by loperamide, and significantly increased the relative abundance of Prevotella and Lactobacillus genera in the stool, while decreased that of Odoribacter, Rikenella, and Parabacteroides. Importantly, L. paracasei NCU-04 also effectively improved the depression-like behaviors associated with constipation, possibly through 5-HT mediated MGBA. These results suggest that L. paracasei NCU-04 may offer a promising approach for treating constipation and its related depressive symptoms, supporting its potential as a functional food or adjuvant therapy for human health.