Primary sclerosing cholangitis (PSC) is a chronic liver disease marked by inflammation of the bile ducts and results in the development of strictures and fibrosis. A robust clinical correlation exists between PSC and inflammatory bowel disease (IBD). At present, published data are controversial, and it is yet unclear whether IBD drives or attenuates PSC.
Abstract Axonemal dynein ATPases direct ciliary and flagellar beating via adenosine triphosphate (ATP) hydrolysis. The modulatory effect of adenosine monophosphate (AMP) and adenosine diphosphate (ADP) on flagellar beating is not fully understood. Here, we describe a deficiency of cilia and flagella associated protein 45 ( CFAP45 ) in humans and mice that presents a motile ciliopathy featuring situs inversus totalis and asthenospermia. CFAP45-deficient cilia and flagella show normal morphology and axonemal ultrastructure. Proteomic profiling links CFAP45 to an axonemal module including dynein ATPases and adenylate kinase as well as CFAP52 , whose mutations cause a similar ciliopathy. CFAP45 binds AMP in vitro, consistent with structural modelling that identifies an AMP-binding interface between CFAP45 and AK8. Microtubule sliding of dyskinetic sperm from Cfap45 −/− mice is rescued with the addition of either AMP or ADP with ATP, compared to ATP alone. We propose that CFAP45 supports mammalian ciliary and flagellar beating via an adenine nucleotide homeostasis module.
Objective There is a strong clinical association between IBD and primary sclerosing cholangitis (PSC), a chronic disease of the liver characterised by biliary inflammation that leads to strictures and fibrosis. Approximately 60%�80% of people with PSC will also develop IBD (PSC-IBD). One hypothesis explaining this association would be that PSC drives IBD. Therefore, our aim was to test this hypothesis and to decipher the underlying mechanism. Design Colitis severity was analysed in experimental mouse models of colitis and sclerosing cholangitis, and people with IBD and PSC-IBD. Foxp3 + Treg-cell infiltration was assessed by qPCR and flow cytometry. Microbiota profiling was carried out from faecal samples of people with IBD, PSC-IBD and mouse models recapitulating these diseases. Faecal microbiota samples collected from people with IBD and PSC-IBD were transplanted into germ-free mice followed by colitis induction. Results We show that sclerosing cholangitis attenuated IBD in mouse models. Mechanistically, sclerosing cholangitis causes an altered intestinal microbiota composition, which promotes Foxp3 + Treg-cell expansion, and thereby protects against IBD. Accordingly, sclerosing cholangitis promotes IBD in the absence of Foxp3 + Treg cells. Furthermore, people with PSC-IBD have an increased Foxp3 + expression in the colon and an overall milder IBD severity. Finally, by transplanting faecal microbiota into gnotobiotic mice, we showed that the intestinal microbiota of people with PSC protects against colitis. Conclusion This study shows that PSC attenuates IBD and provides a comprehensive insight into the mechanisms involved in this effect.
Summary T regulatory type 1 (Tr1) cells, which are defined by their regulatory function, lack of Foxp3, high expression of IL-10, CD49b, and LAG3, are known to be able to suppress Th1 and Th17 in the intestine. Th1 and Th17 cells are also the main drivers of crescentic glomerulonephritis, the most severe form of renal autoimmune disease. However, whether Tr1 cells emerge in renal inflammation and moreover, whether they exhibit regulatory function during glomerulonephritis has not been thoroughly investigated yet. To address these questions, we used a mouse model of experimental crescentic glomerulonephritis and double Foxp3 mRFP IL-10 eGFP reporter mice. We found that Foxp3 neg IL-10-producing CD4 + T cells infiltrate the kidneys during glomerulonephritis progression. Using single-cell RNA- sequencing, we could show that these cells express the core transcriptional factors characteristic of Tr1 cells. In line with this, Tr1 cells showed a strong suppressive activity ex vivo and were protective in experimental crescentic glomerulonephritis in vivo . Finally, we could also identify Tr1 cells in the kidneys of patients with anti-neutrophil cytoplasmic autoantibody (ANCA)-associated glomerulonephritis and define their transcriptional profile. Tr1 cells are currently used in several immune-mediated inflammatory diseases, e.g. as T- cell therapy. Thus, our study provides proof of concept for Tr1 cell-based therapies in experimental glomerulonephritis.
T regulatory type 1 (Tr1) cells, which are defined by their regulatory function, lack of Foxp3, and high expression of IL-10, CD49b, and LAG-3, are known to be able to suppress Th1 and Th17 in the intestine. Th1 and Th17 cells are also the main drivers of crescentic glomerulonephritis (GN), the most severe form of renal autoimmune disease. However, whether Tr1 cells emerge in renal inflammation and, moreover, whether they exhibit regulatory function during GN have not been thoroughly investigated yet. To address these questions, we used a mouse model of experimental crescentic GN and double Foxp3mRFP IL-10eGFP reporter mice. We found that Foxp3neg IL-10-producing CD4+ T cells infiltrate the kidneys during GN progression. Using single-cell RNA sequencing, we could show that these cells express the core transcriptional factors characteristic of Tr1 cells. In line with this, Tr1 cells showed a strong suppressive activity ex vivo and were protective in experimental crescentic GN in vivo. Finally, we could also identify Tr1 cells in the kidneys of patients with antineutrophil cytoplasmic autoantibody-associated GN and define their transcriptional profile. Tr1 cells are currently used in several immune-mediated inflammatory diseases, such as T-cell therapy. Thus, our study provides proof of concept for Tr1 cell-based therapies in experimental GN.
