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It has been shown that p-cresol administration induces social behavior deficits and repetitive behavior in mice. However, the mechanisms of p-cresol, specifically its metabolite pCS that can reach the brain, in ASD remain to be investigated. The pCS has been shown to inhibit LPS-stimulated inflammatory response. A Disintegrin And Metalloprotease 10 (ADAM10) and A Disintegrin And Metalloprotease 17 (ADAM17) are thought to regulate microglial immune response by cleaving membrane-bound proteins. In the present study, a neuroinflammation model of LPS-activated BV2 microglia has been used to unveil the potential molecular mechanism of pCS in ASD pathogenesis. In microglial cells pCS treatment decreases the expression or maturation of ADAM10 and ADAM17. In addition, pCS treatment attenuates TNF-\u03b1 and IL-6 releases as well as phagocytosis activity of microglia. In in vitro ADAM10\/17 inhibition experiments, either ADAM10 or ADAM17 inhibition reduces constitutive and LPS-activated release of TNF-\u03b1, TNFR-1 and IL-6R by microglial cells, while it increases constitutive and LPS-activated microglial phagocytotic activity. The in vivo results further confirm the involvement of ADAM10 and ADAM17 in ASD pathogenesis. In in utero VPA-exposed male mice, elevated concentration in serum of p-cresol-associated metabolites pCS and p-cresyl glucuronide (pCG) is associated with a VPA-induced increased ADAM10 maturation, and a decreased ADAM17 maturation that is related with attenuated levels of soluble TNF-\u03b1 and TGF-\u03b21 in the mice brain. Overall, the present study demonstrates a partial role of ADAM10 and ADAM17 in the derailed innate immune response of microglial cells associated with pCS-induced ASD pathogenesis.<\/jats:p>","DOI":"10.3390\/ijms231911013","type":"journal-article","created":{"date-parts":[[2022,9,20]],"date-time":"2022-09-20T22:36:44Z","timestamp":1663713404000},"page":"11013","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":30,"title":["The Autism Spectrum Disorder-Associated Bacterial Metabolite p-Cresol Derails the Neuroimmune Response of Microglial Cells Partially via Reduction of ADAM17 and ADAM10"],"prefix":"10.3390","volume":"23","author":[{"given":"Yuanpeng","family":"Zheng","sequence":"first","affiliation":[{"name":"Division of Pharmacology, Utrecht Institute for Pharmaceutical Sciences, Faculty of Science, Utrecht University, 3584 CG Utrecht, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Naika Z.","family":"Prince","sequence":"additional","affiliation":[{"name":"Division of Pharmacology, Utrecht Institute for Pharmaceutical Sciences, Faculty of Science, Utrecht University, 3584 CG Utrecht, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1806-5382","authenticated-orcid":false,"given":"Lucia N.","family":"Peralta Marzal","sequence":"additional","affiliation":[{"name":"Division of Pharmacology, Utrecht Institute for Pharmaceutical Sciences, Faculty of Science, Utrecht University, 3584 CG Utrecht, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sabbir","family":"Ahmed","sequence":"additional","affiliation":[{"name":"Division of Pharmacology, Utrecht Institute for Pharmaceutical Sciences, Faculty of Science, Utrecht University, 3584 CG Utrecht, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8678-9182","authenticated-orcid":false,"given":"Johan","family":"Garssen","sequence":"additional","affiliation":[{"name":"Division of Pharmacology, Utrecht Institute for Pharmaceutical Sciences, Faculty of Science, Utrecht University, 3584 CG Utrecht, The Netherlands"},{"name":"Global Centre of Excellence Immunology, Danone-Nutricia Research, 3584 CT Utrecht, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paula","family":"Perez Pardo","sequence":"additional","affiliation":[{"name":"Division of Pharmacology, Utrecht Institute for Pharmaceutical Sciences, Faculty of Science, Utrecht University, 3584 CG Utrecht, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9819-383X","authenticated-orcid":false,"given":"Aletta D.","family":"Kraneveld","sequence":"additional","affiliation":[{"name":"Division of Pharmacology, Utrecht Institute for Pharmaceutical Sciences, Faculty of Science, Utrecht University, 3584 CG Utrecht, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2022,9,20]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"508","DOI":"10.1016\/S0140-6736(18)31129-2","article-title":"Autism spectrum disorder","volume":"392","author":"Lord","year":"2018","journal-title":"Lancet"},{"key":"ref_2","doi-asserted-by":"crossref","unstructured":"Roussin, L., Prince, N., Perez-Pardo, P., Kraneveld, A.D., Rabot, S., and Naudon, L. 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