{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,1]],"date-time":"2026-05-01T03:36:44Z","timestamp":1777606604568,"version":"3.51.4"},"reference-count":48,"publisher":"American Society of Hematology","issue":"16","content-domain":{"domain":["ashpublications.org"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2021,8,24]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Streptococcal pneumonia is a worldwide health problem that kills \u223c2 million people each year, particularly young children, the elderly, and immunosuppressed individuals. Alveolar macrophages and neutrophils provide the early innate immune response to clear pneumococcus from infected lungs. However, the level of neutrophil involvement is context dependent, both in humans and in mouse models of the disease, influenced by factors such as bacterial load, age, and coinfections. Here, we show that the G protein\u2013coupled receptor (GPCR) adaptor protein norbin (neurochondrin, NCDN), which was hitherto known as a regulator of neuronal function, is a suppressor of neutrophil-mediated innate immunity. Myeloid norbin deficiency improved the immunity of mice to pneumococcal infection by increasing the involvement of neutrophils in clearing the bacteria, without affecting neutrophil recruitment or causing autoinflammation. It also improved immunity during Escherichia coli\u2013induced septic peritonitis. It increased the responsiveness of neutrophils to a range of stimuli, promoting their ability to kill bacteria in a reactive oxygen species\u2013dependent manner, enhancing degranulation, phagocytosis, and the production of reactive oxygen species and neutrophil extracellular traps, raising the cell surface levels of selected GPCRs, and increasing GPCR-dependent Rac and Erk signaling. The Rac guanine-nucleotide exchange factor Prex1, a known effector of norbin, was dispensable for most of these effects, which suggested that norbin controls additional downstream targets. We identified the Rac guanine-nucleotide exchange factor Vav as one of these effectors. In summary, our study presents the GPCR adaptor protein norbin as an immune suppressor that limits the ability of neutrophils to clear bacterial infections.<\/jats:p>","DOI":"10.1182\/bloodadvances.2020002782","type":"journal-article","created":{"date-parts":[[2021,8,17]],"date-time":"2021-08-17T15:48:31Z","timestamp":1629215311000},"page":"3076-3091","update-policy":"https:\/\/doi.org\/10.1182\/blood.2019cm0000","source":"Crossref","is-referenced-by-count":18,"title":["The GPCR adaptor protein norbin suppresses the neutrophil-mediated immunity of mice to pneumococcal infection"],"prefix":"10.1182","volume":"5","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-5837-2056","authenticated-orcid":false,"given":"Chiara","family":"Pantarelli","sequence":"first","affiliation":[{"name":"Signalling Programme,"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Dingxin","family":"Pan","sequence":"additional","affiliation":[{"name":"Signalling 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Programme,"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5573-6363","authenticated-orcid":false,"given":"Simon J.","family":"Cleary","sequence":"additional","affiliation":[{"name":"Signalling Programme,"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9743-6294","authenticated-orcid":false,"given":"Martin J.","family":"Baker","sequence":"additional","affiliation":[{"name":"Signalling Programme,"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Elizabeth","family":"Hampson","sequence":"additional","affiliation":[{"name":"Signalling Programme,"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Anna","family":"Mandel","sequence":"additional","affiliation":[{"name":"Signalling Programme,"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Anne","family":"Segonds-Pichon","sequence":"additional","affiliation":[{"name":"Bioinformatics Group, and"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Rachael","family":"Walker","sequence":"additional","affiliation":[{"name":"Flow Cytometry Facility, The Babraham Institute, Babraham Research Campus, Cambridge, United Kingdom;"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Cornelis","family":"van \u2019t Veer","sequence":"additional","affiliation":[{"name":"Center of Experimental and Molecular Medicine, Amsterdam University Medical Center, University of Amsterdam, Amsterdam, The Netherlands; and"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2137-9430","authenticated-orcid":false,"given":"Yanira","family":"Riffo-Vasquez","sequence":"additional","affiliation":[{"name":"Sackler Institute of Pulmonary Pharmacology, Institute of Pharmaceutical Science, King\u2019s College London, London, United Kingdom"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9432-4051","authenticated-orcid":false,"given":"Klaus","family":"Okkenhaug","sequence":"additional","affiliation":[{"name":"Lymphocyte Signalling Programme,"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3961-0407","authenticated-orcid":false,"given":"Simon","family":"Pitchford","sequence":"additional","affiliation":[{"name":"Sackler Institute of Pulmonary Pharmacology, Institute of Pharmaceutical Science, King\u2019s College London, London, United Kingdom"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7865-7000","authenticated-orcid":false,"given":"Heidi C.E.","family":"Welch","sequence":"additional","affiliation":[{"name":"Signalling 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palmitoyl substrates reveals a role for DHHC1\/3\/10 (zDHHC1\/3\/11)-mediated neurochondrin palmitoylation in its targeting to Rab5-positive endosomes","volume":"288","author":"Oku","year":"2013","journal-title":"J Biol Chem."},{"issue":"8","key":"2021081715341335400_B48","doi-asserted-by":"crossref","first-page":"4425","DOI":"10.4049\/jimmunol.171.8.4425","article-title":"The hemopoietic Rho\/Rac guanine nucleotide exchange factor Vav1 regulates N-formyl-methionyl-leucyl-phenylalanine-activated neutrophil functions","volume":"171","author":"Kim","year":"2003","journal-title":"J Immunol."}],"container-title":["Blood 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