{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,20]],"date-time":"2026-04-20T05:53:37Z","timestamp":1776664417249,"version":"3.51.2"},"reference-count":51,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,4,20]],"date-time":"2026-04-20T00:00:00Z","timestamp":1776643200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Mol. Neurosci."],"abstract":"<jats:p>Neuropathic pain is a debilitating chronic condition sustained by maladaptive neuroimmune interactions within the central nervous system, with microglial activation in the spinal dorsal horn serving as a critical driver of pain initiation and chronification. Within this framework, microglial activation mediated by colony-stimulating factor 1 receptor (CSF1R) signaling has emerged as a pathway that is both necessary and sufficient for the development and maintenance of neuropathic pain; however, the upstream mechanisms that determine CSF1R membrane availability and signaling intensity in microglia remain poorly defined. Here, we propose the hypothesis that sphingomyelin synthase 1 (SMS1) functions as a metabolic gatekeeper that amplifies microglial CSF1R signaling by regulating diacylglycerol (DAG)\/protein kinase D (PKD)-dependent receptor trafficking. Following peripheral nerve injury, SMS1 expression is upregulated in spinal microglia, leading to increased Golgi-associated DAG production and subsequent PKD activation. Activated PKD promotes vesicular transport of CSF1R from the Golgi apparatus to the plasma membrane, thereby increasing CSF1R surface density and prolonging receptor signaling. Enhanced CSF1R membrane availability amplifies CSF1-driven microglial proliferation and neuroinflammatory signaling, ultimately facilitating synaptic dysregulation and persistent pain hypersensitivity. This hypothesis establishes a direct mechanistic link between sphingolipid metabolism and microglial neuroimmune signaling and identifies SMS1 as a previously unrecognized upstream regulator of neuropathic pain. Targeting SMS1 may therefore represent a novel therapeutic strategy that modulates microglial activation while avoiding the systemic immune suppression associated with direct CSF1R blockade. If validated, this lipid-regulated trafficking mechanism may have broader implications for other microglia-dependent disorders of the central nervous system.<\/jats:p>","DOI":"10.3389\/fnmol.2026.1798921","type":"journal-article","created":{"date-parts":[[2026,4,20]],"date-time":"2026-04-20T05:24:34Z","timestamp":1776662674000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Sphingomyelin synthase 1 as a potential upstream amplifier of microglial CSF1R signaling in neuropathic pain"],"prefix":"10.3389","volume":"19","author":[{"given":"Minghui","family":"Tan","sequence":"first","affiliation":[{"name":"Department of Encephalopathy, Chongqing Jiulongpo Hospital of Traditional Chinese Medicine, Chongqing University of Chinese Medicine","place":["Chongqing, China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Meiping","family":"Wu","sequence":"additional","affiliation":[{"name":"Department of Orthopedics, Chongqing Jiulongpo Hospital of Traditional Chinese Medicine, Chongqing University of Chinese Medicine","place":["Chongqing, China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Meikui","family":"Wu","sequence":"additional","affiliation":[{"name":"Department of Anesthesiology, National Cancer Center\/National Clinical Research Center for Cancer\/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College","place":["Beijing, China"]}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1965","published-online":{"date-parts":[[2026,4,20]]},"reference":[{"key":"ref1","doi-asserted-by":"publisher","first-page":"101116","DOI":"10.1016\/j.crmeth.2025.101116","article-title":"AAV vectors for specific and efficient gene expression in microglia","volume":"5","author":"Aoki","year":"2025","journal-title":"Cell Rep. 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Life Sci."},{"key":"ref13","doi-asserted-by":"publisher","first-page":"380","DOI":"10.1016\/j.neuron.2014.02.040","article-title":"Colony-stimulating factor 1 receptor signaling is necessary for microglia viability, unmasking a microglia progenitor cell in the adult brain","volume":"82","author":"Elmore","year":"2014","journal-title":"Neuron"},{"key":"ref14","doi-asserted-by":"publisher","first-page":"896","DOI":"10.1016\/j.neuron.2025.01.005","article-title":"Divergent sex-specific pannexin-1 mechanisms in microglia and T cells underlie neuropathic pain","volume":"113","author":"Fan","year":"2025","journal-title":"Neuron"},{"key":"ref15","doi-asserted-by":"publisher","first-page":"675","DOI":"10.1002\/glia.24133","article-title":"Sex-specific transcriptome of spinal microglia in neuropathic pain due to peripheral nerve injury","volume":"70","author":"Fiore","year":"2022","journal-title":"Glia"},{"key":"ref16","doi-asserted-by":"publisher","first-page":"11118","DOI":"10.3390\/ijms262211118","article-title":"The involvement of ceramide, sphingosine-1-phosphate and ganglioside GM1 in regulating some nervous system functions","volume":"26","author":"Giussani","year":"2025","journal-title":"Int. J. Mol. Sci."},{"key":"ref17","doi-asserted-by":"publisher","first-page":"e2118335119","DOI":"10.1073\/pnas.2026494119","article-title":"PKD-dependent PARP12-catalyzed mono-ADP-ribosylation of Golgin-97 is required for E-cadherin transport from Golgi to plasma membrane","volume":"119","author":"Grimaldi","year":"2022","journal-title":"Proc. Natl. Acad. Sci. U.S.A."},{"key":"ref18","doi-asserted-by":"publisher","first-page":"94","DOI":"10.1038\/nn.4189","article-title":"Injured sensory neuron-derived CSF1 induces microglial proliferation and DAP12-dependent pain","volume":"19","author":"Guan","year":"2016","journal-title":"Nat. Neurosci."},{"key":"ref19","doi-asserted-by":"publisher","first-page":"1359","DOI":"10.1038\/s41593-018-0242-x","article-title":"Microglia in neurodegeneration","volume":"21","author":"Hickman","year":"2018","journal-title":"Nat. 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Biol."},{"key":"ref26","doi-asserted-by":"publisher","first-page":"S2","DOI":"10.1097\/j.pain.0000000000000389","article-title":"Sex differences in pain: a tale of two immune cells","volume":"157","author":"Mapplebeck","year":"2016","journal-title":"Pain"},{"key":"ref27","doi-asserted-by":"publisher","first-page":"a009035","DOI":"10.1101\/cshperspect.a009035","article-title":"Effects of membrane trafficking on signaling by receptor tyrosine kinases","volume":"5","author":"Miaczynska","year":"2013","journal-title":"Cold Spring Harb. Perspect. Biol."},{"key":"ref28","doi-asserted-by":"publisher","first-page":"242","DOI":"10.1186\/s12974-023-02924-5","article-title":"Distinguishing the effects of systemic CSF1R inhibition by PLX3397 on microglia and peripheral immune cells","volume":"20","author":"Okojie","year":"2023","journal-title":"J. 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Neurosci."},{"key":"ref39","doi-asserted-by":"publisher","first-page":"e23644","DOI":"10.1371\/journal.pone.0023644","article-title":"Sphingomyelin synthases regulate protein trafficking and secretion","volume":"6","author":"Subathra","year":"2011","journal-title":"PLoS One"},{"key":"ref40","doi-asserted-by":"publisher","first-page":"6406","DOI":"10.1073\/pnas.1219909110","article-title":"Intact sphingomyelin biosynthetic pathway is essential for intracellular transport of influenza virus glycoproteins","volume":"110","author":"Tafesse","year":"2013","journal-title":"Proc. Natl. Acad. Sci. U.S.A."},{"key":"ref41","doi-asserted-by":"publisher","first-page":"328","DOI":"10.1016\/j.bbrc.2009.02.063","article-title":"Sphingomyelin synthase 2 is palmitoylated at the COOH-terminal tail, which is involved in its localization in plasma membranes","volume":"381","author":"Tani","year":"2009","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref42","doi-asserted-by":"publisher","first-page":"843","DOI":"10.1038\/s41467-022-28473-8","article-title":"Single-cell RNA sequencing reveals time- and sex-specific responses of mouse spinal cord microglia to peripheral nerve injury and links ApoE to chronic pain","volume":"13","author":"Tansley","year":"2022","journal-title":"Nat. Commun."},{"key":"ref43","doi-asserted-by":"publisher","first-page":"153","DOI":"10.1016\/j.tins.2022.11.007","article-title":"Microglial diversity in neuropathic pain","volume":"46","author":"Tsuda","year":"2023","journal-title":"Trends Neurosci."},{"key":"ref44","doi-asserted-by":"publisher","first-page":"12960","DOI":"10.1038\/srep12960","article-title":"Asymmetrical diacylglycerol dynamics on the cytosolic and lumenal sides of a single endomembrane in living cells","volume":"5","author":"Ueda","year":"2015","journal-title":"Sci. Rep."},{"key":"ref45","doi-asserted-by":"publisher","first-page":"65","DOI":"10.1146\/annurev-genet-022223-093643","article-title":"Microglial transcriptional signatures in the central nervous system: toward a future of unraveling their function in health and disease","volume":"57","author":"Vecchiarelli","year":"2023","journal-title":"Annu. Rev. Genet."},{"key":"ref46","doi-asserted-by":"publisher","first-page":"31","DOI":"10.1042\/BJ20071240","article-title":"Sphingomyelin synthases regulate production of diacylglycerol at the Golgi","volume":"414","author":"Villani","year":"2008","journal-title":"Biochem. J."},{"key":"ref47","doi-asserted-by":"publisher","first-page":"22","DOI":"10.1016\/j.jmoldx.2011.08.002","article-title":"RNAscope: a novel in situ RNA analysis platform for formalin-fixed, paraffin-embedded tissues","volume":"14","author":"Wang","year":"2012","journal-title":"J. Mol. Diagn."},{"key":"ref48","doi-asserted-by":"publisher","first-page":"1337150","DOI":"10.3389\/fphar.2024.1337150","article-title":"Dysregulation of sphingolipid metabolism in pain","volume":"15","author":"Wang","year":"2024","journal-title":"Front. Pharmacol."},{"key":"ref49","doi-asserted-by":"publisher","first-page":"C15","DOI":"10.1152\/ajpcell.00272.2015","article-title":"Regulation of membrane KCNQ1\/KCNE1 channel density by sphingomyelin synthase 1","volume":"311","author":"Wu","year":"2016","journal-title":"Am. J. Physiol. Cell Physiol."},{"key":"ref50","doi-asserted-by":"publisher","first-page":"89","DOI":"10.1186\/1743-7075-8-89","article-title":"Subcellular targeting domains of sphingomyelin synthase 1 and 2","volume":"8","author":"Yeang","year":"2011","journal-title":"Nutr. 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