American journal of physiology. Cell physiology最新文献

{"title":"O₂-sensing and HIF regulation: from oxygen homeostasis to tumor-associated immune responses.","authors":"Vivienne Schneider, Joachim Fandrey, Sandra Winning","doi":"10.1152/ajpcell.00185.2026","DOIUrl":"10.1152/ajpcell.00185.2026","url":null,"abstract":"<p><p>Oxygen is needed to generate adenosine triphosphate (ATP) via aerobic respiration in mitochondria. Hypoxia-when the tissue's oxygen demand exceeds its supply-characterizes not only sites of acute inflammation but also many tumors and their microenvironment. But even then, (immune) cells must ensure sufficient ATP synthesis. Under hypoxic conditions, hypoxia-inducible factors (HIFs) are capable of adapting cellular metabolism by induction of hundreds of target genes that, among others, regulate glycolysis, cell survival, and angiogenesis. This may hold true for immune cells under homeostatic conditions when they are forced to fight against pathogens and for tumor cells when the activation of HIFs enables tumor cells to survive in oxygen-deficient tissues. In addition, HIF activation in many tumors promotes the creation of an immunosuppressive tumor microenvironment that prevents immune cells from effectively fighting the tumor. Therefore, promising approaches have been made in the combination of immune therapies with HIF inhibition. In this review, we highlight that a better understanding of the role of hypoxic adaptation requires considering the HIF stabilization patterns of tumor type, tumor stage, and the immune cells within the tumor microenvironment to optimize therapeutic efficacy.</p>","PeriodicalId":7585,"journal":{"name":"American journal of physiology. Cell physiology","volume":" ","pages":"C849-C863"},"PeriodicalIF":5.4,"publicationDate":"2026-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148710885","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Cross talk between SARS-CoV-2 and the angiotensin system: clinical implications.","authors":"Safa Kinaneh, Shadi Hamoud, Yara Knany, Samuel N Heyman, Zaid Abassi","doi":"10.1152/ajpcell.00786.2025","DOIUrl":"10.1152/ajpcell.00786.2025","url":null,"abstract":"<p><p>Angiotensin-converting enzyme 2 (ACE2), serving as a receptor to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is a key player in renin-angiotensin-aldosterone system (RAAS). Consequent ACE2 depletion disrupts the balance between the angiotensin II (Ang-II)/angiotensin 1 receptor (AT1R) and angiotensin 1-7 (Ang 1-7)/Mas receptor (MasR) arms of the angiotensin system, promoting intense inflammation. A cross talk existing between the angiotensin system and ACE2/spike proteins that may affect infection severity, with potential therapeutic implications. Evaluating such potential interactions and their relevance to the severity of coronavirus disease 2019 (COVID-19), which is directly affected by ACE2 abundance or indirectly by RAAS axis dysregulation. The intensity of SARS-CoV-2 infection was assessed using a cell-to-cell fusion assay, and AT1R activation was assessed using AT1R-Tango approach. We demonstrate the critical function of ACE2 in mitigating AT1R activation, which is disrupted following SARS-CoV-2 infection. Moreover, we show that the spike protein indirectly intensifies AT1R activation. Beyond its established role in activating MasR, Ang 1-7 was found to function as a biased agonist for AT1R, without altering ACE2 levels or affecting SARS-CoV-2 entry. In contrast, AVE0991, a MasR agonist, was observed to increase ACE2 levels and enhance SARS-CoV-2 infection. Angiotensin receptor blockers (ARBs) effectively inhibited AT1R activity and had minimal impact on viral entry. Our data support the likelihood that AT1R blockers (ARBs) may be effective in managing COVID-19 since they inhibit AT1R activation and its deleterious subsequent effects, with no impact on SARS-CoV-2 entry. By contrast, MasR and its agonist AVE0991, by increasing ACE2 levels, may restore RAAS physiological balance, but facilitate host cell invasion by SARS-CoV-2.<b>NEW & NOTEWORTHY</b> This study characterizes the interaction between the angiotensin system and angiotensin-converting enzyme 2 (ACE2)/spike proteins and its significance for coronavirus disease 2019 (COVID-19) severity. Using a cell-to-cell fusion assay and angiotensin 1 receptor (AT1R) activation assessment via the AT1R-Tango approach, we reveal a crucial role of ACE2 in attenuating AT1R activation. Furthermore, the data indicate that the spike protein indirectly amplifies AT1R activation. In addition, angiotensin 1-7 (Ang 1-7) was identified to act not only as Mas receptor (MasR) agonist, but also as a biased agonist for AT1R.</p>","PeriodicalId":7585,"journal":{"name":"American journal of physiology. Cell physiology","volume":" ","pages":"C982-C998"},"PeriodicalIF":5.4,"publicationDate":"2026-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148879042","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Extracellular cues and cellular conversations: the molecular choreography of embryo implantation.","authors":"Janice K Jeschke, Verena Nordhoff, Martin Götte, Konstantina Kyriakopoulou","doi":"10.1152/ajpcell.00048.2026","DOIUrl":"10.1152/ajpcell.00048.2026","url":null,"abstract":"<p><p>Infertility affects millions of people globally with recent statistics indicating that one in six adults is experiencing reproductive challenges at some point. For female infertility in particular, the global health burden is continuously intensifying with significant disparities across countries. Female infertility has a complex multifactorial etiology, and understanding the underlying mechanisms is crucial to reduce the health burden and enhance patient well-being. For a pregnancy, successful embryo implantation is a pivotal step, requiring precise spatiotemporal synchronization between a competent blastocyst and a receptive endometrium during the window of implantation (WOI). This review provides an overview of recent developments around the molecular and clinical aspects of this process, with a specific focus on the extracellular microenvironmental cues and maternal-embryo interaction. Specifically, we detail the extensive extracellular matrix (ECM) remodeling that facilitates embryo adhesion and invasion while shedding light on microRNAs as signaling and communication mediators that govern cell-cell and maternal-fetal interactions. Finally, we examine current limitations in the clinical assessment of receptivity and discuss future perspectives for noninvasive biomarkers and possibilities for more personalized solutions in assisted reproduction.</p>","PeriodicalId":7585,"journal":{"name":"American journal of physiology. Cell physiology","volume":" ","pages":"C1047-C1060"},"PeriodicalIF":5.4,"publicationDate":"2026-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148872709","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Human M1 macrophages secrete glutamine: a role for the transporters ASCT2 and SNAT5.","authors":"Giuseppe Taurino, Martina Chiu, Chiara Ughini, Chiara Maccari, Roberta Andreoli, Giulia Longhi, Marco Ventura, Ovidio Bussolati, Massimiliano G Bianchi","doi":"10.1152/ajpcell.00055.2026","DOIUrl":"10.1152/ajpcell.00055.2026","url":null,"abstract":"<p><p>Previous results indicated that LPS treatment of human macrophages is associated with the induction of glutamate-ammonia-ligase (GLUL), the enzyme that synthesizes glutamine (Gln), although the effects on cell Gln level were not assessed by those studies. Here, we show that M1 polarization of human THP-1 macrophage-like cells with LPS and interferon γ (IFNγ) induces not only GLUL but also the exchange Gln transporter ASCT2 and the bidirectional carrier SNAT5. Consequently, Gln influx markedly increases, with ASCT2 and SNAT5 inhibitors suppressing the effect. Notwithstanding these changes, cell Gln is comparable in human M0 and M1 macrophages. However, under Gln-free conditions, Gln efflux is threefold faster in M1 macrophages. With the same approach, we have demonstrated that cell glutamate (Glu) mostly derives from extracellular Gln. Furthermore, Glu efflux is markedly higher in M1 macrophages, consistent with the induction of the Glu-cystine exchanger xCT. Induction of GLUL, SNAT5, and xCT, along with SNAT5-dependent stimulation of Gln transport, are clearly detectable also in primary human macrophages, derived from monocytes of peripheral blood and M1-polarized with LPS/IFNγ. These data indicate that, through a stimulation of Gln and Glu efflux, M1-polarized human macrophages can increase the concentration of both amino acids in the extracellular microenvironment.<b>NEW & NOTEWORTHY</b> M1 polarization of human macrophages promotes the induction of glutamate-ammonia-ligase (GLUL) and of the Gln transporters SNAT5 and ASCT2, leading to a faster efflux of the amino acid into the extracellular compartment. Under the same conditions, induction of the transporter xCT mediates the increased efflux of glutamate. Therefore, M1 macrophages can increase the extracellular concentrations of both glutamine and glutamate, potentially influencing the metabolic and functional behavior of other cell populations present in the microenvironment.</p>","PeriodicalId":7585,"journal":{"name":"American journal of physiology. Cell physiology","volume":" ","pages":"C864-C876"},"PeriodicalIF":5.4,"publicationDate":"2026-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148705460","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Endogenous calcium/calmodulin-dependent protein kinase II gamma and delta maintain type II myofiber identity in adult mice.","authors":"Hikaru Iwase, Yuka Ichihashi, Ryoka Tsukahara, Takuma Kunieda, Yuki Maeda, Yasuo Uchida, Tomoharu Yasuda, Yasuo Kitajima","doi":"10.1152/ajpcell.00464.2026","DOIUrl":"10.1152/ajpcell.00464.2026","url":null,"abstract":"<p><p>Skeletal muscle fiber identity is commonly characterized by coordinated contractile and metabolic programs, but the mechanisms that preserve this coordination in adult muscle remain unclear. We tested whether endogenous calcium/calmodulin-dependent protein kinase II γ and δ (CaMKIIγ/δ) maintain type II myofiber identity. Tamoxifen-inducible, skeletal muscle-specific <i>Camk2g/Camk2d</i> double-knockout mice were analyzed 1 and 3 mo after deletion using soleus fiber typing, laser microdissection proteomics, and immunofluorescence. CaMKIIγ/δ deletion was not associated with detectable changes in body weight or muscle mass but increased type I fibers and reduced total type II fibers at both time points, with a transient increase in type I/II hybrid fibers. Within muscles of knockout mice, the type IIa fiber proportion declined over time. Fiber type-resolved proteomics revealed remodeling within fibers retaining a type II myosin heavy chain profile. Proteins enriched in control type I fibers shifted upward in knockout type II fibers, whereas type II-enriched proteins shifted downward. Consistently, a type I-like score derived from an independent single-myofiber proteomic dataset increased selectively in knockout type II fibers, supporting remodeling beyond myosin isoform switching. CaMKII abundance was higher in type II than in type I fibers. Unexpectedly, this type I-like remodeling was not accompanied by an oxidative shift: oxidative phosphorylation-related protein programs were reduced across type I, type II, and hybrid fibers. These findings identify endogenous CaMKIIγ/δ as a homeostatic regulator of adult type II myofiber identity and show that fiber identity-associated proteomic features and mitochondrial oxidative programs can be remodeled in divergent directions.<b>NEW & NOTEWORTHY</b> CaMKII is activated by contraction-associated calcium signals, but the role of endogenous CaMKIIγ/δ in preserving adult myofiber identity was unknown. Using inducible muscle-specific deletion and fiber type-resolved proteomics, we show that endogenous CaMKIIγ/δ maintains type II myofiber identity. Its loss drives type I-like remodeling within myosin heavy chain-defined type II fibers while reducing mitochondrial oxidative protein programs, revealing that fiber identity-associated proteomic features and mitochondrial oxidative protein programs can be remodeled in partially uncoupled directions.</p>","PeriodicalId":7585,"journal":{"name":"American journal of physiology. Cell physiology","volume":" ","pages":"C1128-C1144"},"PeriodicalIF":5.4,"publicationDate":"2026-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148975503","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"High-intensity interval training via electrical stimulation enhances endurance by preserving sarcoplasmic reticulum Ca²⁺ transients in mouse skeletal muscle.","authors":"Luke D Flewwelling, Masih Jafari, Shahrzad Khajehzadehshoushtar, Takashi Yamada, Christopher G R Perry, Arthur J Cheng","doi":"10.1152/ajpcell.00795.2025","DOIUrl":"10.1152/ajpcell.00795.2025","url":null,"abstract":"<p><p>This study investigated the effects of high-intensity interval training (HIIT) or low-intensity interval training (LIIT) via electrical stimulation (ES) on muscle performance, specifically focusing on fatigue resistance and cytoplasmic-free calcium ([Ca²⁺]_i) dynamics in mouse skeletal muscle. Thirty female C57BL6 mice (9 wk old) underwent 4 wk of involuntary interval training with electrical stimulation (IT-ES) in hindlimb plantar flexor muscles in vivo, with stimulation frequencies set at either 20 Hz (LIIT) or 100 Hz (HIIT). Our results showed that IT-ES significantly enhanced fatigue resistance, particularly with HIIT, evidenced by improved muscle torque output and better preservation of tetanic [Ca²⁺]_i levels during repeated contractions. In addition, IT-ES led to increases in sarcoplasmic reticulum (SR) Ca²⁺-handling proteins, such as SR Ca²⁺ ATPase 1 (SERCA1) and the ryanodine receptor 1 (RyR1), as well as mitochondrial respiratory complex proteins, indicating enhanced metabolic adaptations. The results suggest that HIIT-ES is an effective intervention for improving muscle function, intracellular Ca²⁺ management, and mitochondrial content, providing a foundation for future consideration in rehabilitation and clinical settings.<b>NEW & NOTEWORTHY</b> We show that 4 wk of high-intensity interval training (HIIT) or low-intensity interval training (LIIT) via electrical stimulation (ES) improves fatigue resistance in mice via enhanced sarcoplasmic reticulum (SR) Ca²⁺ transients and increased mitochondrial complex protein content. This study demonstrates the mechanisms by which fatigue resistance is improved with chronic electrical stimulation interval training exercise.</p>","PeriodicalId":7585,"journal":{"name":"American journal of physiology. Cell physiology","volume":" ","pages":"C1027-C1036"},"PeriodicalIF":5.4,"publicationDate":"2026-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148886191","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Effects of cytoplasmic free Mg²⁺ buffering on skeletal muscle fatigue in intact single mouse muscle fibers.","authors":"Daiki Watanabe, Nathaniel J Andrews, Ihtisham A Rana, Aditya N Brahmbhatt, Christopher G R Perry, Arthur J Cheng","doi":"10.1152/ajpcell.00435.2026","DOIUrl":"https://doi.org/10.1152/ajpcell.00435.2026","url":null,"abstract":"<p><p>Changes in cytoplasmic free Mg²⁺ concentration ([Mg²⁺]_cyto) might play a key role in regulating skeletal muscle function. Mag-indo-1, a fluorescence dye that specifically binds to Mg²⁺, can be used both to detect and buffer [Mg²⁺]_cyto. In this study, we hypothesized that buffering the fatigue-induced elevations in [Mg²⁺]_cyto would mitigate fatigue by preserving sarcoplasmic reticulum (SR) Ca²⁺ release. Intact fibers were isolated from the flexor digitorum brevis muscle, and loaded with varying concentration of Mag-indo-1-AM. The fibers were repeatedly stimulated at 70 Hz for 300 msec every 2 sec for 100 contractions (fatiguing stimulation: FS). To examine the relationship between fatigue and Mg²⁺ buffering, we compared the force produced during the final contraction of FS with the amount of Mag-indo-1 loading before FS (Fatigue-Mg²⁺ buffer relationship). Fatigue-Mg²⁺ buffer relationship exhibited an inverted U-shaped curve: fatigue resistance improved when [Mag-indo-1] increased up to an optimal level, but declined when [Mag-indo-1] became excessive. Therefore, the fibers were classified into three groups: underloaded, optimal-loaded and overloaded groups. Caffeine treatment immediately after FS significantly enhanced force recovery in the underloaded group, reaching a level comparable to that of caffeine-treated, optimal-loaded group. Furthermore, mitochondrial coupled respiration was impaired, and proton leak was enhanced in the presence of nM level Mag-indo-1. These results suggest that elevated [Mg²⁺]_cyto contributes to muscle fatigue due to impairments of SR Ca²⁺ release. Conversely, excessive buffering of [Mg²⁺]_cyto may also exacerbate muscle fatigue, indicating that a proper [Mg²⁺]_cyto balance is critical for maintaining fatigue resistance.</p>","PeriodicalId":7585,"journal":{"name":"American journal of physiology. Cell physiology","volume":" ","pages":""},"PeriodicalIF":5.4,"publicationDate":"2026-09-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149079380","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Inhibition of PDGF signal suppresses the fibrotic scar formation and promotes axonal regeneration in a mouse nigrostriatal lesion model.","authors":"Yukari Komuta, Junko Kimura-Kuroda, Yuko Seko, Yu Hongo, Kazushi Suzuki, Hitoshi Kawano","doi":"10.1152/ajpcell.00386.2026","DOIUrl":"https://doi.org/10.1152/ajpcell.00386.2026","url":null,"abstract":"<p><p>After traumatic injury to the central nervous system (CNS), meningeal fibroblasts migrate into the lesion site and synthesize extracellular matrix (ECM) molecules, leading to the formation of a fibrotic scar (FS). The FS prevents axonal regeneration by releasing inhibitory ECMs, including chondroitin sulfate proteoglycans, Slits, and semaphorin 3A. Platelet-derived growth factor (PDGF) has been implicated in fibrotic diseases, but its specific contribution to FS formation has remained unclear. In this study, we investigated the role of PDGF signaling in scar formation after CNS injury. In the lesioned mouse brain, PDGFRα and PDGFRβ were strongly expressed within the FS, while PDGF-B was detected in reactive astrocytes surrounding the lesion. Administration of AG1296, a PDGF signaling inhibitor, into the lesion site significantly reduced FS formation and allowed partial regeneration of transected dopaminergic axons. Complementary in vitro studies using rat meningeal fibroblasts demonstrated that PDGF signaling promoted both proliferation and migration of fibroblasts. Moreover, PDGF stimulation enhanced expression of transforming growth factor-β (TGF-β), a cytokine known to drive ECM deposition and scar formation. These findings provide the first direct evidence that inhibition of PDGF signaling suppresses FS formation and facilitates axonal regeneration after CNS lesioning. Our results suggest that PDGF signaling functions during the early phase of FS development by promoting fibroblast proliferation, migration, and TGF-β expression. Thus, targeting PDGF signaling may represent a promising therapeutic strategy for limiting scar formation and improving neural repair following human CNS injury.</p>","PeriodicalId":7585,"journal":{"name":"American journal of physiology. Cell physiology","volume":" ","pages":""},"PeriodicalIF":5.4,"publicationDate":"2026-09-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149079365","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Microbial-Derived Exerkines as a Model of Drug Discovery.","authors":"Benjamin I Burke, Taylor R Valentino, Ahmed Ismaeel, Yuan Wen, John J McCarthy","doi":"10.1152/ajpcell.90006.2026","DOIUrl":"https://doi.org/10.1152/ajpcell.90006.2026","url":null,"abstract":"<p><p>There has been a growing interest in the utilization of the gut microbiome as a therapeutic tool. The relationship between the gut microbiome and exercise provides a unique opportunity to maximize the therapeutic capacity of the gut microbiome. Here, we summarize the potential of leveraging the gut microbiome to confer the health benefits of exercise through a novel class of microbial metabolites termed microbial-derived exerkines (MDEs). We identify multiple candidate and established MDEs described in the literature (e.g., pipecolic acid, succinate, short-chain fatty acids, indole-3-propionic acid, 3-hydroxyphenylacetic acid) and explore their implications in conditions such as inflammatory bowel disease, aging, skeletal muscle atrophy, cancer, diabetes, cardiovascular disease, and Alzheimer's disease. Given the beneficial effects of exercise on numerous diseases, we anticipate MDEs will be a productive avenue for drug discovery and therapeutic progress.</p>","PeriodicalId":7585,"journal":{"name":"American journal of physiology. Cell physiology","volume":" ","pages":""},"PeriodicalIF":5.4,"publicationDate":"2026-09-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149079423","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Autonomic-Immune Crosstalk in Lupus: Impaired Cholinergic Signaling and Consequences for Cardiovascular-Renal Physiology.","authors":"Keisa W Mathis, Paromita Das-Earl, Kayla Nguyen-Alley, Antonia Bruce","doi":"10.1152/ajpcell.00111.2026","DOIUrl":"https://doi.org/10.1152/ajpcell.00111.2026","url":null,"abstract":"<p><p>Over the years, our group has used complementary approaches to examine how autonomic-immune crosstalk influences the pathogenesis of systemic lupus erythematosus (SLE). We found that pharmacological enhancement of vagal activity and engagement of the parasympathetically-mediated cholinergic anti-inflammatory pathway via systemic administration of galantamine attenuated pathogenic autoantibodies, blood pressure and inflammatory mediators in murine lupus. With longer administration, galantamine also attenuated splenic B cells and renal fibrosis, and improved survival. Complementary B cell depletion studies in the same mouse model supported an important role for B-cell-dependent autoimmunity in hypertension and kidney injury in lupus, providing mechanistic context for why cholinergic anti-inflammatory pathway-targeted interventions are effective. In contrast, direct localized chemogenetic stimulation of efferent parasympathetic neurons in the dorsal motor nucleus of the vagus did not alter blood pressure or autoantibody levels but improved renal pathology in lupus mice. Similarly, bilateral denervation of renal sympathetic nerves did not affect blood pressure or autoantibody production but reduced albuminuria in lupus mice. Together, these studies demonstrate that direct modulation of autonomic nerve activity can selectively influence kidney outcomes and that a precise balance between parasympathetic and sympathetic signaling is required to maintain immune cell and inflammatory homeostasis. Disruption of this balance may contribute to chronic inflammatory diseases such as SLE and others. This review highlights emerging opportunities for cholinergic anti-inflammatory pathway-based pharmacological and neuromodulatory strategies to mitigate inflammation-driven autoimmune, cardiovascular, and renal disease.</p>","PeriodicalId":7585,"journal":{"name":"American journal of physiology. Cell physiology","volume":" ","pages":""},"PeriodicalIF":5.4,"publicationDate":"2026-09-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149036181","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}