{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,5,7]],"date-time":"2026-05-07T00:14:10Z","timestamp":1778112850051,"version":"3.51.4"},"posted":{"date-parts":[[2024,1,5]]},"group-title":"Immunology","reference-count":76,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2024,1,5]],"date-time":"2024-01-05T00:00:00Z","timestamp":1704412800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/www.biorxiv.org\/about\/FAQ#license"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2024,8,13]]},"abstract":"<jats:p>Sensory neurons sense pathogenic infiltration, serving to inform immune coordination of host defense. However, sensory neuron-immune interactions have been predominantly shown to drive innate immune responses. Humoral memory, whether protective or destructive, is acquired early in life - as demonstrated by both early exposure to streptococci and allergic disease onset. Our study further defines the role of sensory neuron influence on humoral immunity in the lung. Using a murine model of Streptococcus pneumonia pre-exposure and infection and a model of allergic asthma, we show that sensory neurons are required for B-cell and plasma cell recruitment and antibody production. In response to S. pneumoniae, sensory neuron depletion resulted in a larger bacterial burden, reduced B-cell populations, IgG release and neutrophil stimulation. Conversely, sensory neuron depletion reduced B-cell populations, IgE and asthmatic characteristics during allergen-induced airway inflammation. The sensory neuron neuropeptide released within each model differed. With bacterial infection, vasoactive intestinal polypeptide (VIP) was preferentially released, whereas substance P was released in response to asthma. Administration of VIP into sensory neuron-depleted mice suppressed bacterial burden and increased IgG levels, while VIP1R deficiency increased susceptibility to bacterial infection. Sensory neuron-depleted mice treated with substance P increased IgE and asthma, while substance P genetic ablation resulted in blunted IgE, similar to sensory neuron-depleted asthmatic mice. These data demonstrate that the immunogen differentially stimulates sensory neurons to release specific neuropeptides which specifically target B-cells. Targeting sensory neurons may provide an alternate treatment pathway for diseases involved with insufficient and\/or aggravated humoral immunity.<\/jats:p>","DOI":"10.1101\/2024.01.04.574231","type":"posted-content","created":{"date-parts":[[2024,1,5]],"date-time":"2024-01-05T11:23:13Z","timestamp":1704453793000},"source":"Crossref","is-referenced-by-count":2,"title":["Sensory neurons regulate stimulus-dependent humoral immunity"],"prefix":"10.64898","author":[{"given":"Diane","family":"Aguilar","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Fengli","family":"Zhu","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Antoine","family":"Millet","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Nicolas","family":"Millet","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Patrizia","family":"Germano","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Joseph","family":"Pisegna","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Omid","family":"Akbari","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Taylor A","family":"Doherty","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5261-6267","authenticated-orcid":false,"given":"Marc","family":"Swidergall","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4342-1839","authenticated-orcid":false,"given":"Nicholas","family":"Jendzjowsky","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"54368","reference":[{"key":"2024020801001151000_2024.01.04.574231v2.1","doi-asserted-by":"publisher","DOI":"10.1038\/nature12479"},{"key":"2024020801001151000_2024.01.04.574231v2.2","doi-asserted-by":"crossref","first-page":"417","DOI":"10.1038\/nm.4501","article-title":"Nociceptor sensory neurons suppress neutrophil and \u03b3\u03b4 T cell responses in bacterial lung infections and lethal pneumonia","volume":"24","year":"2018","journal-title":"Nat Med"},{"key":"2024020801001151000_2024.01.04.574231v2.3","doi-asserted-by":"publisher","DOI":"10.10l6\/j.cell.2018.04.006"},{"key":"2024020801001151000_2024.01.04.574231v2.4","doi-asserted-by":"publisher","DOI":"10.1038\/nature13199"},{"key":"2024020801001151000_2024.01.04.574231v2.5","doi-asserted-by":"crossref","first-page":"1978","DOI":"10.1093\/infdis\/jiaa014","article-title":"Sensory Nociceptive Neurons Contribute to Host Protection During Enteric Infection With Citrobacter rodentium","volume":"221","year":"2020","journal-title":"The Journal of Infectious Diseases"},{"key":"2024020801001151000_2024.01.04.574231v2.6","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.95.6.3251"},{"key":"2024020801001151000_2024.01.04.574231v2.7","doi-asserted-by":"crossref","first-page":"515","DOI":"10.1016\/j.immuni.2015.08.016","article-title":"Nociceptive Sensory Fibers Drive Interleukin-23 Production from CD301b+ Dermal Dendritic Cells and Drive Protective Cutaneous Immunity","volume":"43","year":"2015","journal-title":"Immunity"},{"key":"2024020801001151000_2024.01.04.574231v2.8","doi-asserted-by":"crossref","first-page":"341","DOI":"10.1016\/j.neuron.2015.06.007","article-title":"Silencing Nociceptor Neurons Reduces Allergic Airway Inflammation","volume":"87","year":"2015","journal-title":"Neuron"},{"key":"2024020801001151000_2024.01.04.574231v2.9","doi-asserted-by":"crossref","first-page":"2330","DOI":"10.1016\/j.jaci.2020.12.644","article-title":"Fc\u03b5R1-expressing nociceptors trigger allergic airway inflammation","volume":"147","year":"2021","journal-title":"J Allergy Clin Immunol"},{"key":"2024020801001151000_2024.01.04.574231v2.10","doi-asserted-by":"crossref","first-page":"e148510","DOI":"10.1172\/jci.insight.148510","article-title":"Nociceptor neurons promote IgE class switch in B cells","volume":"6","year":"2021","journal-title":"JCI Insight"},{"key":"2024020801001151000_2024.01.04.574231v2.11","doi-asserted-by":"publisher","DOI":"10.1016\/j.immuni.2020.10.001"},{"key":"2024020801001151000_2024.01.04.574231v2.12","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2017.08.006"},{"key":"2024020801001151000_2024.01.04.574231v2.13","doi-asserted-by":"publisher","DOI":"10.1113\/JP280749"},{"key":"2024020801001151000_2024.01.04.574231v2.14","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuroscience.2011.06.085"},{"key":"2024020801001151000_2024.01.04.574231v2.15","doi-asserted-by":"publisher","DOI":"10.1038\/s41590-019-0493-z"},{"key":"2024020801001151000_2024.01.04.574231v2.16","doi-asserted-by":"publisher","DOI":"10.1186\/1744-8069-6-61"},{"key":"2024020801001151000_2024.01.04.574231v2.17","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.2022087118"},{"key":"2024020801001151000_2024.01.04.574231v2.18","doi-asserted-by":"crossref","first-page":"80","DOI":"10.1016\/j.jneuroim.2009.01.008","article-title":"Immunoglobulin-free light chains mediate antigen-specific responses of murine dorsal root ganglion neurons","volume":"208","year":"2009","journal-title":"J. Neuroimmunol"},{"key":"2024020801001151000_2024.01.04.574231v2.19","doi-asserted-by":"crossref","unstructured":"Cui, H. et al. Neuronal Fc\u03b5RI\u03b1 directly mediates ocular itch via IgE-immune complex in a mouse model of allergic conjunctivitis. Journal of Neuroinflammation 19, 55 (2022).","DOI":"10.1186\/s12974-022-02417-x"},{"key":"2024020801001151000_2024.01.04.574231v2.20","doi-asserted-by":"publisher","DOI":"10.1096\/fj.02-1169fje"},{"key":"2024020801001151000_2024.01.04.574231v2.21","doi-asserted-by":"publisher","DOI":"10.1038\/s41583-021-00555-4"},{"key":"2024020801001151000_2024.01.04.574231v2.22","doi-asserted-by":"crossref","first-page":"777","DOI":"10.1016\/j.it.2017.02.007","article-title":"The S(c)ensory Immune System Theory","volume":"38","year":"2017","journal-title":"Trends Immunol"},{"key":"2024020801001151000_2024.01.04.574231v2.23","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2017.02.009"},{"key":"2024020801001151000_2024.01.04.574231v2.24","doi-asserted-by":"crossref","first-page":"33","DOI":"10.1016\/j.cell.2019.11.014","article-title":"Gut-Innervating Nociceptor Neurons Regulate Peyer\u2019s Patch Microfold Cells and SFB Levels to Mediate Salmonella Host Defense","volume":"180","year":"2020","journal-title":"Cell"},{"key":"2024020801001151000_2024.01.04.574231v2.25","doi-asserted-by":"crossref","unstructured":"Blake, K. J. et al. Staphylococcus aureus produces pain through pore-forming toxins and neuronal TRPV1 that is silenced by QX-314. Nat Commun 9, (2018).","DOI":"10.1038\/s41467-017-02448-6"},{"key":"2024020801001151000_2024.01.04.574231v2.26","doi-asserted-by":"publisher","DOI":"10.1038\/nature23469"},{"key":"2024020801001151000_2024.01.04.574231v2.27","doi-asserted-by":"crossref","unstructured":"Foster, S. L. , Seehus, C. R. , Woolf, C. J. & Talbot, S . Sense and Immunity: Context-Dependent Neuro-Immune Interplay. Front Immunol 8, (2017).","DOI":"10.3389\/fimmu.2017.01463"},{"key":"2024020801001151000_2024.01.04.574231v2.28","doi-asserted-by":"crossref","first-page":"627","DOI":"10.1038\/mi.2014.95","article-title":"Protection against Streptococcus pneumoniae lung infection after nasopharyngeal colonization requires both humoral and cellular immune responses","volume":"8","year":"2015","journal-title":"Mucosal Immunology"},{"key":"2024020801001151000_2024.01.04.574231v2.29","doi-asserted-by":"publisher","DOI":"10.1128\/IAI.01275-15"},{"key":"2024020801001151000_2024.01.04.574231v2.30","doi-asserted-by":"publisher","DOI":"10.1084\/jem.20111941"},{"key":"2024020801001151000_2024.01.04.574231v2.31","doi-asserted-by":"publisher","DOI":"10.1038\/nri1181"},{"key":"2024020801001151000_2024.01.04.574231v2.32","doi-asserted-by":"crossref","first-page":"2130","DOI":"10.4049\/jimmunol.146.7.2130","article-title":"Substance P acts directly upon cloned B lymphoma cells to enhance IgA and IgM production","volume":"146","year":"1991","journal-title":"J Immunol"},{"key":"2024020801001151000_2024.01.04.574231v2.33","doi-asserted-by":"crossref","first-page":"292","DOI":"10.1111\/apa.13684","article-title":"Neuropeptide Y receptor 1 is expressed by B and T lymphocytes and mast cells in infantile haemangiomas","volume":"106","year":"2017","journal-title":"Acta Paediatr"},{"key":"2024020801001151000_2024.01.04.574231v2.34","doi-asserted-by":"publisher","DOI":"10.1006\/cimm.1993.1207"},{"key":"2024020801001151000_2024.01.04.574231v2.35","doi-asserted-by":"publisher","DOI":"10.1016\/S0165-5728(98)00043-5"},{"key":"2024020801001151000_2024.01.04.574231v2.36","doi-asserted-by":"publisher","DOI":"10.1016\/0008-8749(92)90257-P"},{"key":"2024020801001151000_2024.01.04.574231v2.37","doi-asserted-by":"publisher","DOI":"10.1002\/eji.1830240950"},{"key":"2024020801001151000_2024.01.04.574231v2.38","doi-asserted-by":"crossref","first-page":"804","DOI":"10.1016\/j.imbio.2019.08.006","article-title":"Vasoactive intestinal peptide alleviates food allergy via restoring regulatory B cell functions","volume":"224","year":"2019","journal-title":"Immunobiology"},{"key":"2024020801001151000_2024.01.04.574231v2.39","doi-asserted-by":"crossref","first-page":"1372","DOI":"10.1161\/CIRCRESAHA.118.314518","article-title":"Glucocorticoids Regulate Bone Marrow B Lymphopoiesis After Stroke","volume":"124","year":"2019","journal-title":"Circ Res"},{"key":"2024020801001151000_2024.01.04.574231v2.40","doi-asserted-by":"publisher","DOI":"10.1016\/S0165-5728(01)00328-9"},{"key":"2024020801001151000_2024.01.04.574231v2.41","doi-asserted-by":"publisher","DOI":"10.1038\/mi.2007.14"},{"key":"2024020801001151000_2024.01.04.574231v2.42","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-020-2235-7"},{"key":"2024020801001151000_2024.01.04.574231v2.43","doi-asserted-by":"publisher","DOI":"10.1038\/35093019"},{"key":"2024020801001151000_2024.01.04.574231v2.44","doi-asserted-by":"publisher","DOI":"10.1016\/j.mcn.2009.10.006"},{"key":"2024020801001151000_2024.01.04.574231v2.45","doi-asserted-by":"publisher","DOI":"10.2174\/156802611796904924"},{"key":"2024020801001151000_2024.01.04.574231v2.46","doi-asserted-by":"publisher","DOI":"10.1038\/nn.3881"},{"key":"2024020801001151000_2024.01.04.574231v2.47","doi-asserted-by":"crossref","unstructured":"Kim, S.-H. et al. Mapping of the Sensory Innervation of the Mouse Lung by Specific Vagal and Dorsal Root Ganglion Neuronal Subsets. eNeuro 9, (2022).","DOI":"10.1523\/ENEURO.0026-22.2022"},{"key":"2024020801001151000_2024.01.04.574231v2.48","doi-asserted-by":"crossref","first-page":"L50","DOI":"10.1152\/ajplung.00376.2021","article-title":"Identification of lung innervating sensory neurons and their target specificity","volume":"322","year":"2022","journal-title":"Am J Physiol Lung Cell Mol Physiol"},{"key":"2024020801001151000_2024.01.04.574231v2.49","doi-asserted-by":"crossref","first-page":"4220","DOI":"10.3390\/ijms20174220","article-title":"Animal Models of Pneumococcal pneumonia","volume":"20","year":"2019","journal-title":"International Journal of Molecular Sciences"},{"key":"2024020801001151000_2024.01.04.574231v2.50","doi-asserted-by":"crossref","unstructured":"Gogos, A. & Federle, M. J . Modeling Streptococcus pyogenes Pharyngeal Colonization in the Mouse. Frontiers in Cellular and Infection Microbiology 9, (2019).","DOI":"10.3389\/fcimb.2019.00137"},{"key":"2024020801001151000_2024.01.04.574231v2.51","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.5788-12.2013"},{"key":"2024020801001151000_2024.01.04.574231v2.52","doi-asserted-by":"publisher","DOI":"10.1016\/j.it.2022.01.003"},{"key":"2024020801001151000_2024.01.04.574231v2.53","doi-asserted-by":"crossref","first-page":"2508","DOI":"10.1016\/j.celrep.2019.04.096","article-title":"An Atlas of Vagal Sensory Neurons and Their Molecular Specialization","volume":"27","year":"2019","journal-title":"Cell Reports"},{"key":"2024020801001151000_2024.01.04.574231v2.54","doi-asserted-by":"publisher","DOI":"10.1016\/0008-8749(91)90284-I"},{"key":"2024020801001151000_2024.01.04.574231v2.55","doi-asserted-by":"crossref","first-page":"2130","DOI":"10.4049\/jimmunol.146.7.2130","article-title":"Substance P acts directly upon cloned B lymphoma cells to enhance IgA and IgM production","volume":"146","year":"1991","journal-title":"J Immunol"},{"key":"2024020801001151000_2024.01.04.574231v2.56","doi-asserted-by":"crossref","first-page":"C537","DOI":"10.1152\/ajpcell.1992.262.3.C537","article-title":"Substance P: a late-acting B lymphocyte differentiation cofactor","volume":"262","year":"1992","journal-title":"Am J Physiol"},{"key":"2024020801001151000_2024.01.04.574231v2.57","doi-asserted-by":"publisher","DOI":"10.1016\/S0165-5728(98)00043-5"},{"key":"2024020801001151000_2024.01.04.574231v2.58","doi-asserted-by":"crossref","first-page":"107","DOI":"10.1016\/S0960-5428(96)00004-6","article-title":"Vasoactive intestinal peptide differentially modulates human immunoglobulin production","volume":"6","year":"1996","journal-title":"Adv Neuroimmunol"},{"key":"2024020801001151000_2024.01.04.574231v2.59","doi-asserted-by":"publisher","DOI":"10.1016\/S0165-5728(02)00278-3"},{"key":"2024020801001151000_2024.01.04.574231v2.60","doi-asserted-by":"publisher","DOI":"10.1152\/ajplung.00174.2012"},{"key":"2024020801001151000_2024.01.04.574231v2.61","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2020.11.028"},{"key":"2024020801001151000_2024.01.04.574231v2.62","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-020-2235-7"},{"key":"2024020801001151000_2024.01.04.574231v2.63","doi-asserted-by":"publisher","DOI":"10.2119\/molmed.2012.00027"},{"key":"2024020801001151000_2024.01.04.574231v2.64","doi-asserted-by":"crossref","first-page":"e72116","DOI":"10.7554\/eLife.72116","article-title":"Protein kinase C\u03b4 is essential for the IgG response against T-cell-independent type 2 antigens and commensal bacteria","volume":"10","year":"2021","journal-title":"eLife"},{"key":"2024020801001151000_2024.01.04.574231v2.65","doi-asserted-by":"publisher","DOI":"10.1196\/annals.1254.014"},{"key":"2024020801001151000_2024.01.04.574231v2.66","doi-asserted-by":"publisher","DOI":"10.1016\/j.jaci.2013.11.027"},{"key":"2024020801001151000_2024.01.04.574231v2.67","doi-asserted-by":"crossref","first-page":"18","DOI":"10.15424\/bioelectronmed.2016.00001","article-title":"Neuronal Circuits Modulate Antigen Flow Through Lymph Nodes","volume":"3","year":"2016","journal-title":"Bioelectron Med"},{"key":"2024020801001151000_2024.01.04.574231v2.68","doi-asserted-by":"crossref","first-page":"555363","DOI":"10.3389\/fimmu.2020.555363","article-title":"Mucosal IgA Prevents Commensal Candida albicans Dysbiosis in the Oral Cavity","volume":"11","year":"2020","journal-title":"Front Immunol"},{"key":"2024020801001151000_2024.01.04.574231v2.69","doi-asserted-by":"publisher","DOI":"10.1038\/s41590-018-0260-6"},{"key":"2024020801001151000_2024.01.04.574231v2.70","doi-asserted-by":"crossref","first-page":"282","DOI":"10.1089\/vim.2019.0141","article-title":"Resident Memory B Cells","volume":"33","year":"2020","journal-title":"Viral Immunol"},{"key":"2024020801001151000_2024.01.04.574231v2.71","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.1801208"},{"key":"2024020801001151000_2024.01.04.574231v2.72","doi-asserted-by":"publisher","DOI":"10.1002\/eji.200939798"},{"key":"2024020801001151000_2024.01.04.574231v2.73","doi-asserted-by":"crossref","first-page":"1432","DOI":"10.1016\/j.jaci.2019.07.018","article-title":"Unconventional ST2- and CD127-negative lung ILC2 populations are induced by the fungal allergen Alternaria alternata","volume":"144","year":"2019","journal-title":"J Allergy Clin Immunol"},{"key":"2024020801001151000_2024.01.04.574231v2.74","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1411032111"},{"key":"2024020801001151000_2024.01.04.574231v2.75","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1501372112"},{"key":"2024020801001151000_2024.01.04.574231v2.76","doi-asserted-by":"crossref","unstructured":"Chiu, H. , et al. Reduced eIF4E function impairs B-cell leukemia without altering normal B-lymphocyte function. iScience 24, (2021).","DOI":"10.1016\/j.isci.2021.102748"}],"container-title":[],"original-title":[],"link":[{"URL":"https:\/\/syndication.highwire.org\/content\/doi\/10.1101\/2024.01.04.574231","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,1,15]],"date-time":"2026-01-15T05:45:37Z","timestamp":1768455937000},"score":1,"resource":{"primary":{"URL":"http:\/\/biorxiv.org\/lookup\/doi\/10.1101\/2024.01.04.574231"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,1,5]]},"references-count":76,"URL":"https:\/\/doi.org\/10.1101\/2024.01.04.574231","relation":{},"subject":[],"published":{"date-parts":[[2024,1,5]]},"subtype":"preprint"}}