{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T12:24:16Z","timestamp":1785414256995,"version":"3.56.0"},"posted":{"date-parts":[[2026,1,20]]},"group-title":"Neuroscience","reference-count":34,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2026,1,20]],"date-time":"2026-01-20T00:00:00Z","timestamp":1768867200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/www.biorxiv.org\/about\/FAQ#license"}],"funder":[{"award":["R01DK108127"],"award-info":[{"award-number":["R01DK108127"]}],"id":[{"id":"https:\/\/ror.org\/001d55x84","id-type":"ROR","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2026,4,9]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                <jats:sec>\n                  <jats:title>Background<\/jats:title>\n                  <jats:p>Immune checkpoint receptors regulate adaptive immunity but are increasingly recognized as modulators of neuroimmune interactions. The upstream signals that induce neuronal checkpoint pathways during inflammation and their functional relevance in inflammatory pain remain incompletely understood. We investigated whether a defined commensal-derived molecule engages a neuroimmune checkpoint axis to modulate inflammatory pain.<\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Methods<\/jats:title>\n                  <jats:p>\n                    SELTA, a lipoteichoic acid purified from a commensal\n                    <jats:italic>Staphylococcus epidermidis<\/jats:italic>\n                    strain, was evaluated for TLR2-dependent activity, regulation of Pdcd1 transcription and PD-1 protein expression in dorsal root ganglion (DRG) neurons, effects on intracellular calcium signaling, and behavioral outcomes in experimental autoimmune prostatitis (EAP) a model of inflammation-induced chronic pelvic pain. Conditional Pdcd1 deletion was performed in sensory neurons (Advillin-\n                    <jats:sup>Cre<\/jats:sup>\n                    ) and CD4\u207a T cells to determine cell-specific requirements.\n                  <\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Results<\/jats:title>\n                  <jats:p>\n                    SELTA selectively activated TLR2\/6 signaling and increased Pdcd1 transcription and PD-1 protein expression in DRG neurons under inflammatory conditions. SELTA enhanced phosphorylation of PD-1 at tyrosine 248 and significantly reduced ATP-evoked intracellular Ca\u00b2\u207a responses in mouse primary sensory neurons. Pharmacologic neutralization of PD-1 abrogated SELTA-mediated suppression of calcium signaling. In vivo, SELTA produced concentration-dependent attenuation of pelvic hypersensitivity in EAP. Conditional deletion of PD-1\n                    <jats:italic>in vivo<\/jats:italic>\n                    in Advillin-expressing sensory neurons or CD4\u207a T cells significantly reduced SELTA-induced analgesia, while combined deletion did not further diminish the effect.\n                  <\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Conclusions<\/jats:title>\n                  <jats:p>These findings identify a commensal-derived lipoteichoic acid that engages a TLR2\/6-associated pathway linked to inducible neuronal PD-1 signaling to restrain inflammatory nociceptor activity. The results define a neuroimmune checkpoint mechanism that modulates inflammatory pain and extend PD-1 signaling beyond its established role in adaptive immunity.<\/jats:p>\n                <\/jats:sec>","DOI":"10.64898\/2026.01.16.699990","type":"posted-content","created":{"date-parts":[[2026,1,21]],"date-time":"2026-01-21T02:05:12Z","timestamp":1768961112000},"source":"Crossref","is-referenced-by-count":0,"title":["A Commensal-Derived Lipoteichoic Acid Engages an Inducible Neuronal PD-1 Checkpoint to Suppress Inflammatory Pain"],"prefix":"10.64898","author":[{"given":"Zhiqiang","family":"Liu","sequence":"first","affiliation":[{"name":"Department of Urology, Northwestern University Feinberg School of Medicine, Chicago, IL, United States"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yen-Hsin","family":"Cheng","sequence":"additional","affiliation":[{"name":"Department of Neuroscience, Northwestern University Feinberg School of Medicine, Chicago, IL, United States"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Catherine V.","family":"Osborn","sequence":"additional","affiliation":[{"name":"Department of Urology, Northwestern University Feinberg School of Medicine, Chicago, IL, United States"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9648-2918","authenticated-orcid":false,"given":"Marco","family":"Martina","sequence":"additional","affiliation":[{"name":"Department of Neuroscience, Northwestern University Feinberg School of Medicine, Chicago, IL, United States"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1324-3517","authenticated-orcid":false,"given":"Anthony J.","family":"Schaeffer","sequence":"additional","affiliation":[{"name":"Department of Urology, Northwestern University Feinberg School of Medicine, Chicago, IL, United States"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5454-4172","authenticated-orcid":false,"given":"Praveen","family":"Thumbikat","sequence":"additional","affiliation":[{"name":"Department of Urology, Northwestern University Feinberg School of Medicine, Chicago, IL, United States"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"54368","reference":[{"key":"2026041108450447000_2026.01.16.699990v2.1","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-019-53463-0"},{"key":"2026041108450447000_2026.01.16.699990v2.2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2014.03.011"},{"key":"2026041108450447000_2026.01.16.699990v2.3","doi-asserted-by":"publisher","DOI":"10.1038\/nn.4571"},{"key":"2026041108450447000_2026.01.16.699990v2.4","doi-asserted-by":"publisher","DOI":"10.1016\/j.urology.2008.11.007"},{"issue":"1","key":"2026041108450447000_2026.01.16.699990v2.5","doi-asserted-by":"crossref","first-page":"50","DOI":"10.1177\/20494637211015265","article-title":"Pain in chronic prostatitis and the role of ion channels: a brief overview","volume":"16","year":"2022","journal-title":"British Journal of Pain"},{"key":"2026041108450447000_2026.01.16.699990v2.6","doi-asserted-by":"publisher","DOI":"10.1016\/j.neulet.2008.01.070"},{"key":"2026041108450447000_2026.01.16.699990v2.7","doi-asserted-by":"publisher","DOI":"10.15585\/mmwr.mm6736a2"},{"issue":"1","key":"2026041108450447000_2026.01.16.699990v2.8","doi-asserted-by":"crossref","first-page":"51","DOI":"10.1186\/s13578-024-01227-3","article-title":"PD-L1\/PD-1 pathway: a potential neuroimmune target for pain relief","volume":"14","year":"2024","journal-title":"Cell Biosci"},{"key":"2026041108450447000_2026.01.16.699990v2.9","doi-asserted-by":"publisher","DOI":"10.1016\/0166-4328(88)90157-X"},{"key":"2026041108450447000_2026.01.16.699990v2.10","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuint.2014.05.012"},{"key":"2026041108450447000_2026.01.16.699990v2.11","doi-asserted-by":"crossref","unstructured":"Hunter DV , Smaila BD , Lopes DM , Takatoh J , Denk F , Ramer MS . 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