Dataset Information

Genetic Deletion of LRP5 and LRP6 in Macrophages Exacerbates Colitis-Associated Systemic Inflammation and Kidney Injury in Response to Intestinal Commensal Microbiota.

ABSTRACT: Extraintestinal manifestations are common in inflammatory bowel disease and involve several organs, including the kidney. However, the mechanisms responsible for renal manifestation in inflammatory bowel disease are not known. In this study, we show that the Wnt-lipoprotein 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-induced 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 LRP5/6^LysM 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 LRP5/6^LysM 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-LRP5/6 signaling in macrophages controls colitis-induced systemic inflammation and AKI.

SUBMITTER: Manoharan I

PROVIDER: S-EPMC9387749 | biostudies-literature | 2022 Jul

REPOSITORIES: biostudies-literature

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Genetic Deletion of LRP5 and LRP6 in Macrophages Exacerbates Colitis-Associated Systemic Inflammation and Kidney Injury in Response to Intestinal Commensal Microbiota.

Manoharan Indumathi I Swafford Daniel D Shanmugam Arulkumaran A Patel Nikhil N Prasad Puttur D PD Mohamed Riyaz R Wei Qingqing Q Dong Zheng Z Thangaraju Muthusamy M Manicassamy Santhakumar S

Journal of immunology (Baltimore, Md. : 1950) 20220627 2

Extraintestinal manifestations are common in inflammatory bowel disease and involve several organs, including the kidney. However, the mechanisms responsible for renal manifestation in inflammatory bowel disease are not known. In this study, we show that the Wnt-lipoprotein 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-induced colitis mode ...[more]

PMID: 35760519

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Project description:Toll-like receptor 4 (TLR4) has been identified as a potentially promising therapeutic target in acute pancreatitis (AP). However, the role of intestinal TLR4 in AP and AP-associated gut injury remains unclear. This study aimed to explore the relationship between intestinal TLR4 and gut microbiota during AP. A mouse AP model was establish by intraperitoneal injection of L-arginine. Pancreatic injury and intestinal barrier function were evaluated in wild-type and intestinal epithelial TLR4 knockout (TLR4ΔIEC) mice. Gut microbiota was analyzed by 16S rRNA sequencing. Quadruple antibiotics were applied to induce microbiota-depleted mice. Differentially expressed genes in gut were detected by RNA sequencing. L. reuteri treatment was carried out in vivo and vitro study. Compared with wild-type mice, AP and AP-associated gut injury were exacerbated in TLR4ΔIEC mice in a gut microbiota-dependent manner. The relative abundance of Lactobacillus and number of Paneth cells remarkably decreased in TLR4ΔIEC mice. The KEGG pathway analysis derived from RNA sequencing suggested that genes affected by intestinal TLR4 deletion were related to the activation of nod-like receptor pathway. Furthermore, L. reuteri treatment could significantly improve the pancreatic and intestinal injury in TLR4ΔIEC mice through promoting Paneth cells in a NOD2-dependent manner. Loss of intestinal epithelial TLR4 exacerbated pancreatic and intestinal damage during AP, which might be attributed to the gut microbiota dysbiosis especially the exhausted Lactobacillus. L. reuteri might maintain intestinal homeostasis and alleviate AP via Paneth cells modulation.Abbreviations: AP Acute pancreatitis, TLR4 Toll-like receptor 4, IL-1β Interleukin-1β, IL-6 Interleukin-6, TNF-α Tumor necrosis factor-α, SIRS Systematic inflammatory response syndrome, LPS Lipopolysaccharides, SPF Specific pathogen-free, ZO-1 Zonula occludens-1, CON Control, H&E Hematoxylin and eosin, FISH Fluorescence in situ hybridization, DAPI 4',6-diamidino-2-phenylindole, PCoA Principal co-ordinates analysis, SCFA Short chain fatty acid, LEfSe Linear discriminant analysis Effect Size, ANOVA Analysis of variance, F/B Firmicutes/Bacteroidetes, PCA Principal component analysis, NOD2 Nod-like receptor 2, ABX antibiotics, PCNA proliferating cell nuclear antigen.

Project description:The cysteine knot protein sclerostin is an osteocyte-derived secreted inhibitor of the Wnt co-receptors LRP5 and LRP6. LRP5 plays a dominant role in bone homeostasis, but we previously reported that Sost/sclerostin suppression significantly increased osteogenesis regardless of Lrp5 presence or absence. Those observations suggested that the bone forming effects of sclerostin inhibition can occur through Lrp6 (when Lrp5 is suppressed), or through other yet undiscovered mechanisms independent of Lrp5/6. To distinguish between these two possibilities, we generated mice with compound deletion of Lrp5 and Lrp6 selectively in bone, and treated them with sclerostin monoclonal antibody (Scl-mAb). All mice were homozygous flox for both Lrp5 and Lrp6 (Lrp5f/f; Lrp6f/f), and varied only in whether or not they carried the Dmp1-Cre transgene. Positive (Cre+) and negative (Cre-) mice were injected with Scl-mAb or vehicle from 4.5 to 14 weeks of age. Vehicle-treated Cre+ mice exhibited significantly reduced skeletal properties compared to vehicle-treated Cre- mice, as assessed by DXA, μCT, pQCT, and histology, indicating that Lrp5/6 deletions were effective and efficient. Scl-mAb treatment improved nearly every bone-related parameter among Cre- mice, but the same treatment in Cre+ mice resulted in little to no improvement in skeletal properties. For the few endpoints where Cre+ mice responded to Scl-mAb, it is likely that antibody-induced promotion of Wnt signaling occurred in cell types earlier in the mesenchymal/osteoblast differentiation pathway than the Dmp1-expressing stage. This latter conclusion was supported by changes in some histomorphometric parameters. In conclusion, unlike with the deletion of Lrp5 alone, the bone-selective late-stage co-deletion of Lrp5 and Lrp6 significantly impairs or completely nullifies the osteogenic action of Scl-mAb, and highlights a major role for both Lrp5 and Lrp6 in the mechanism of action for the bone-building effects of sclerostin antibody.

Dataset Information

Genetic Deletion of LRP5 and LRP6 in Macrophages Exacerbates Colitis-Associated Systemic Inflammation and Kidney Injury in Response to Intestinal Commensal Microbiota.

Publications

Genetic Deletion of LRP5 and LRP6 in Macrophages Exacerbates Colitis-Associated Systemic Inflammation and Kidney Injury in Response to Intestinal Commensal Microbiota.

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