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However, the mechanisms responsible for renal manifestation in inflammatory bowel disease are not known. In this study, we show that the Wnt\u2013lipoprotein receptor-related proteins 5 and 6 (LRP5\/6) signaling pathway in macrophages plays a critical role in regulating colitis-associated systemic inflammation and renal injury in a murine dextran sodium sulfate\u2013induced colitis model. Conditional deletion of the Wnt coreceptors LRP5\/6 in macrophages in mice results in enhanced susceptibility to dextran sodium sulfate colitis-induced systemic inflammation and acute kidney injury (AKI). Furthermore, our studies show that aggravated colitis-associated systemic inflammation and AKI observed in LRP5\/6LysM mice are due to increased bacterial translocation to extraintestinal sites and microbiota-dependent increased proinflammatory cytokine levels in the kidney. Conversely, depletion of the gut microbiota mitigated colitis-associated systemic inflammation and AKI in LRP5\/6LysM mice. Mechanistically, LRP5\/6-deficient macrophages were hyperresponsive to TLR ligands and produced higher levels of proinflammatory cytokines, which are associated with increased activation of MAPKs. These results reveal how the Wnt\u2013LRP5\/6 signaling in macrophages controls colitis-induced systemic inflammation and AKI.<\/jats:p>","DOI":"10.4049\/jimmunol.2101172","type":"journal-article","created":{"date-parts":[[2022,7,14]],"date-time":"2022-07-14T16:26:01Z","timestamp":1657815961000},"page":"368-378","source":"Crossref","is-referenced-by-count":7,"title":["Genetic Deletion of LRP5 and LRP6 in Macrophages Exacerbates Colitis-Associated Systemic Inflammation and Kidney Injury in Response to Intestinal Commensal Microbiota"],"prefix":"10.1093","volume":"209","author":[{"given":"Indumathi","family":"Manoharan","sequence":"first","affiliation":[{"name":"Department of Biochemistry and Molecular Biology, Medical College of Georgia, Augusta University , Augusta, GA"},{"name":"Georgia Cancer Center, Medical College of Georgia, Augusta University , Augusta, GA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniel","family":"Swafford","sequence":"additional","affiliation":[{"name":"Georgia Cancer Center, Medical College of Georgia, Augusta University , Augusta, GA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Arulkumaran","family":"Shanmugam","sequence":"additional","affiliation":[{"name":"Georgia Cancer Center, Medical College of Georgia, Augusta University , Augusta, GA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9335-0082","authenticated-orcid":false,"given":"Nikhil","family":"Patel","sequence":"additional","affiliation":[{"name":"Department of Pathology, Medical College of Georgia, Augusta University , Augusta, GA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8455-0186","authenticated-orcid":false,"given":"Puttur D","family":"Prasad","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Molecular Biology, Medical College of Georgia, Augusta University , Augusta, GA"},{"name":"Georgia Cancer Center, Medical College of Georgia, Augusta University , Augusta, GA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2398-3057","authenticated-orcid":false,"given":"Riyaz","family":"Mohamed","sequence":"additional","affiliation":[{"name":"Department of Physiology, Medical College of Georgia, Augusta University , Augusta, GA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1692-2451","authenticated-orcid":false,"given":"Qingqing","family":"Wei","sequence":"additional","affiliation":[{"name":"Department of Cellular Biology and Anatomy, Medical College of Georgia, Augusta University , Augusta, GA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zheng","family":"Dong","sequence":"additional","affiliation":[{"name":"Department of Cellular Biology and Anatomy, Medical College of Georgia, Augusta University , Augusta, GA"},{"name":"Research Department, Charlie Norwood VA Medical Center , Augusta, GA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Muthusamy","family":"Thangaraju","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Molecular Biology, Medical College of Georgia, Augusta University , Augusta, GA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2203-3917","authenticated-orcid":false,"given":"Santhakumar","family":"Manicassamy","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Molecular Biology, Medical College of Georgia, Augusta University , Augusta, GA"},{"name":"Georgia Cancer Center, Medical College of Georgia, Augusta University , Augusta, GA"},{"name":"Department of Medicine, Medical College of Georgia, Augusta University , Augusta, GA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2022,7,15]]},"reference":[{"key":"2025021008213693400_r1","first-page":"235","article-title":"Extraintestinal manifestations of inflammatory bowel disease","volume":"7","author":"Levine","year":"2011","journal-title":"Gastroenterol. 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