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Paneth cell-derived intestinal luminal lysozyme shapes mucolytic microbiota and controls mucosal inflammatory tone

ABSTRACT: Paneth cells are the primary, and possibly the sole, source of lysozyme in the intestinal lumen. Mice lacking the Paneth cell lysozyme gene, Lyz1, had diminished NLR signaling and basal inflammation, and were further protected from experimental colitis. Protection depended on an enhanced goblet and tuft cell program that was driven by IL13-IL4Ra-Stat6 signaling and required an expansion of lysozyme-sensitive mucolytic bacteria. Forced ectopic lysozyme production in colonic epithelium suppressed these bacteria and exacerbated colitis. Single cell RNA-seq of Lyz1 KO lamina propria revealed an activated ILC2 profile towards cytokine production. One lysozymesensitive species, Ruminococcus gnavus , when processed by lysozyme, induced a pro-inflammatory response, while non-processed R. gnavus stimulated IL13 production in lymphocytes. Consistent with a role of lysozyme for cell-wall processing in the inflammatory response, Lyz1 KO microbiota was anti-colitogenic in lysozymedeficient hosts but colitogenic in lysozyme-sufficient hosts. Thus, Paneth cell lysozyme regulates inflammatory tone by modulating mucosal response to specific bacterial groups.

ORGANISM(S): Mus musculus

PROVIDER: GSE151151 | GEO | 2020/08/19

REPOSITORIES: GEO

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Transcriptional profiling of ileal lamina propria lymphocytes of wild type and Lyz1KO mice by single-cell RNA-seq

Project description:Paneth cells express Lyz1, a gene encoding for lysozyme. To investigate the transcriptomic profiles of wild type and Lyz1-knockout mouse ileal lamina propria cells, we performed single-cell RNA-seq.

2020-08-19 | GSE151152 | GEO

Targeted transcriptome analysis of isolated intestinal epithelial cells from mice with constitutive Ptpn2-deficiency

Project description:Background & aims: Loss-of-function variants in the PTPN2 gene are associated with increased risk of inflammatory bowel disease. We recently showed that Ptpn2 is critical for intestinal epithelial cell (IEC) barrier maintenance, IEC-macrophage communication, and modulation of the gut microbiome in mice, restricting expansion of a small intestinal pathobiont associated with inflammatory bowel disease. Here, we aimed to identify how Ptpn2 loss affects ileal IEC subtypes and their function in vivo. Methods: Constitutive Ptpn2 wild-type, heterozygous, and knockout (KO) mice, as well as mice with inducible deletion of Ptpn2 in IECs, were used in the study. Investigation was performed using imaging techniques, flow cytometry, enteroid culture, and analysis of gene and protein levels of IEC markers. Results: Partial transcriptome analysis showed that expression of Paneth cell-associated antimicrobial peptides Lyz1, Pla2g2a, and Defa6 was down-regulated markedly in Ptpn2-KO mice compared with wild-type and heterozygous. In parallel, Paneth cell numbers were reduced, their endoplasmic reticulum architecture was disrupted, and the endoplasmic reticulum stress protein, C/EBP-homologous protein (CHOP), was increased in Ptpn2-KO mice. Despite reduced Paneth cell number, flow cytometry showed increased expression of the Paneth cell-stimulatory cytokines interleukin 22 and interferon γ+ in CD4+ T cells isolated from Ptpn2-KO ileum. Key findings in constitutive Ptpn2-KO mice were confirmed in epithelium-specific Ptpn2ΔIEC mice, which also showed impaired lysozyme protein levels in Paneth cells compared with Ptpn2fl/fl control mice. Conclusions: Constitutive Ptpn2 deficiency affects Paneth cell viability and compromises Paneth cell-specific antimicrobial peptide production. The observed effects may contribute to the increased susceptibility to intestinal infection and dysbiosis in these mice.

2023-04-10 | GSE181923 | GEO

Paneth cell scRNA-seq analysis of un-infected and Salmonella Typhimurium infected mice

Project description:Paneth cells consist of heterogeous phenotypes. How Paneth cells respond to infection by invasive pathogenic bacteria at single cell level remains uncharacterized. We used a flow cytometry based method to isolate Paneth cells from uninfected and Salmonella-infected Paneth cell reporter mice (Lyz1-3'UTR-IRES-CreER; Rosa26R-tdTomato). These highly pure Paneth cell populations were used for single cell RNA sequencing analysis.

2023-09-01 | GSE237326 | GEO

Single cell RNA sequencing analysis of germ free (GF) mouse Paneth cells and microbiome-transferred exGF mouse Paneth cells.

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Mouse duodenal and ileal Paneth cell single cell RNA sequencing

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2023-09-01 | GSE237327 | GEO

Paneth cell-derived intestinal luminal lysozyme shapes mucolytic microbiota and controls mucosal inflammatory tone

Project description:Paneth cell-derived intestinal luminal lysozyme shapes mucolytic microbiota and controls mucosal inflammatory tone

| PRJNA634896 | ENA

RNA-Sequence analysis of enteroids incubating with Bifidobacterium longum

Project description:Although oral administration of Bifidobacterium longum (B. longum) relieves irritable bowel syndrome (IBS) symptoms in a clinical setting, the underlying mechanisms remain undetermined. Herein, we confirmed that B. longum ameliorated defecation habits and alleviated visceral hypersensitivity in water avoidance stress (WAS) rats. Further analysis revealed that B. longum enhanced mucosal repair, promoted the production of lysozyme, and ameliorated microbiota dysbiosis in WAS rats. These activities are all closely correlated with Paneth cell function. In vitro, we incubated primary cultured enteroids with B. longum and found that this bacterium promoted the proliferation of these organoids, which may be attributed to the up-regulated expression of the stem niche factors WNT3A and TGF-β which are serected by the Paneth cells. On the basis of our findings, we propose that B. longum relieves IBS by restoring the antimicrobial activity and stem niche maintenance functions of Paneth cells.

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IL13 and CCL2 Drive Disease in an Inflammatory Subset of Scleroderma

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2011-06-30 | E-GEOD-24410 | biostudies-arrayexpress

SLC7A5 is critical for Paneth cell integrity and function

Project description:The intestine is the critical organ not only for processing and resorbing nutrients from ingested food but also for defending the organism from external stresses such as pathogens. These functions are mainly carried out by the epithelium which is constantly being self-renewed throughout adult life. Intestinal epithelial homeostasis is maintained through well-controlled cell proliferation of the stem cells and transient amplifying cells and the apoptotic degeneration of epithelial cells, mostly at or near the tip of the villi. Many genes and pathways have been found to influence intestinal epithelial cell proliferation. Among them is the mTORC1 signaling pathway, whose activation is known to increase cell proliferation. Here, we report the first intestinal epithelial specific knockout (IEC-KO) of an amino acid transporter capable of activating mTORC1. We show that the transporter, slc7a5, is highly expressed in the intestinal crypt and slc7a5 IEC-KO leads to expected reduction in mTORC1 signal in the crypt or even in intestinal organoids in vitro. Surprisingly, slc7a5 IEC-KO leads to increased proliferation of both transit amplifying cells and crypt base stem cells but a reduction in the secretory cells, particularly mature Paneth cells in the crypt base. Our scRNA-seq and electron microscopic analyses reveals that slc7a5 IEC-KO causes dedifferentiation of the Paneth cells, leading to drastically reduced secretory granules and lysozyme expression without affecting the overall Paneth cell number. We further show that slc7a5 IEC-KO mice are prone to induced colitis due to this loss of Paneth cell differentiation. We propose a model where slc7a5 regulates secretory cell differentiation to affect stem cell niche and/or inflammatory response to regulate cell proliferation in the crypts.

2024-04-24 | GSE216930 | GEO

IL13 and CCL2 drive disease in an inflammatory subset of Scleroderma [IL13]

Project description:Scleroderma is a lethal and currently irreversible autoimmune disease characterized by widespread tissue fibrosis and vasculopathy. Using cross-species comparative gene expression profiling we show that murine sclerodematous graft-versus-host disease (sclGVHD) approximates an “inflammatory” subset of human scleroderma and that both diseases demonstrate activation of the IL13 cytokine pathway. We report that both host myeloid cells expressing type I and II activated macrophage markers and graft T-cells produce IL13 and that host mice deficient in either IL13 or IL4Ra, an IL13 signal transducer, are protected from disease. This signaling pathway converges on a single gene, CCL2, which is coordinately upregulated in sclGVHD, in the human inflammatory scleroderma subset and in IL13 treated human dermal fibroblasts. Accordingly, treatment with antibodies to CCL2, and its murine homolog CCL12, prevent sclGVHD. Lastly, we provide evidence that IL13 pathway activation in early scleroderma patients correlates with modified Rodnan skin scores (mRSS). These data indicate that an inflammatory subset of scleroderma is driven by IL13 and may benefit from IL13 or CCL2 blockade. sample vs reference. Total RNA isolated from a time course of primary adult dermal fibroblasts treated with 50nM recombinant IL13 over 24 hours

2011-06-30 | E-GEOD-24403 | biostudies-arrayexpress

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