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Epithelial colonization by gut dendritic cells promotes their functional diversification.

ABSTRACT: Dendritic cells (DCs) patrol tissues and transport antigens to lymph nodes to initiate adaptive immune responses. Within tissues, DCs constitute a complex cell population composed of distinct subsets that can exhibit different activation states and functions. How tissue-specific cues orchestrate DC diversification remains elusive. Here, we show that the small intestine included two pools of cDC2s originating from common pre-DC precursors: (1) lamina propria (LP) CD103⁺CD11b⁺ cDC2s that were mature-like proinflammatory cells and (2) intraepithelial cDC2s that exhibited an immature-like phenotype as well as tolerogenic properties. These phenotypes resulted from the action of food-derived retinoic acid (ATRA), which enhanced actomyosin contractility and promoted LP cDC2 transmigration into the epithelium. There, cDC2s were imprinted by environmental cues, including ATRA itself and the mucus component Muc2. Hence, by reaching distinct subtissular niches, DCs can exist as immature and mature cells within the same tissue, revealing an additional mechanism of DC functional diversification.

SUBMITTER: Rivera CA

PROVIDER: S-EPMC8751639 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Epithelial Colonization by Gut Dendritic Cells promotes their Functional Diversification

Project description:Dendritic cells (DCs) patrol tissues and transport antigens to lymph nodes to initiate adaptive immune responses. Within tissues, DCs constitute a complex cell population composed of distinct subsets that can exhibit different activation states and functions. How tissue-specific cues orchestrate DC diversification remains elusive. Here, we show that the small intestine included two pools of cDC2s originating from common preDC precursors: (1) lamina propria (LP) CD103+CD11b+ cDC2s that were mature-like pro-inflammatory cells and (2) intraepithelial cDC2s that exhibited an immature-like phenotype as well as tolerogenic properties. These phenotypes resulted from the action of food-derived retinoic acid (ATRA), which enhanced actomyosin contractility and promoted LP cDC2 transmigration into the epithelium. There, cDC2s were imprinted by environmental cues including ATRA itself and the mucus component Muc2. Hence, by reaching distinct sub-tissular niches, DCs can exist as immature and mature cells within the same tissue, revealing an additional mechanism of DC functional diversification.

2021-11-11 | GSE188379 | GEO

Epithelial Colonization by Gut Dendritic Cells promotes their Functional Diversification

Project description:Epithelial Colonization by Gut Dendritic Cells promotes their Functional Diversification

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Unexpected mutual regulation underlies paralogue functional diversification and promotes epithelial tissue maturation in Tribolium.

Project description:Insect Hox3/zen genes represent an evolutionary hotspot for changes in function and copy number. Single orthologues are required either for early specification or late morphogenesis of the extraembryonic tissues, which protect the embryo. The tandemly duplicated zen paralogues of the beetle Tribolium castaneum present a unique opportunity to investigate both functions in a single species. We dissect the paralogues' expression dynamics (transcript and protein) and transcriptional targets (RNA-seq after RNAi) throughout embryogenesis. We identify an unexpected role of Tc-Zen2 in repression of Tc-zen1, generating a negative feedback loop that promotes developmental progression. Tc-Zen2 regulation is dynamic, including within co-expressed multigene loci. We also show that extraembryonic development is the major event within the transcriptional landscape of late embryogenesis and provide a global molecular characterization of the extraembryonic serosal tissue. Altogether, we propose that paralogue mutual regulation arose through multiple instances of zen subfunctionalization, leading to their complementary extant roles.

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LNCGM1082 in Gut Epithelial Cells Promotes Expulsion of Infected Epithelial Cells and Release of IL-18.

Project description:Inflammasome NLRC4 (NLR family CARD domain containing 4) can protect mucosal barriers such as intestine from invading bacterial pathogens. However, it was incompletely clear how NLRC4 was activated in intestinal epithelial cells. In this study, we demonstrated that LNCGM1082 could mediate the activation of NLRC4 via binding NLRC4 with protein kinase C (PKC)δ. LNCGM1082 knockout (KO) mice had reduced resistance against Salmonella Typhimurium infection, as well as impaired expulsion of infected gut epithelial cells and release of IL-18 upon exposure to S. Typhimurium. Similar to NLRC4 KO and PKCδ knockdown gut organoids, there also was impaired expulsion of gut epithelial cells and release of IL-18 in LNCGM1082 KO gut organoids. Furthermore, there also was reduced activation of caspase-1 and caspase-8 in these LNCGM1082 KO, NLRC4 KO, and PKCδ knockdown gut organoids upon exposure to S. Typhimurium. Our results show that LNCGM1082 in the ICEs plays a critical role in mediating activation of NLRC4 through binding NLRC4 and PKCδ and promoting expulsion of infected epithelial cells and release of IL-18 upon exposure to bacteria such as S. Typhimurium.

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Age-mediated gut microbiota dysbiosis promotes the loss of dendritic cells tolerance.

Project description:The old age-related loss of immune tolerance inflicts a person with a wide range of autoimmune and inflammatory diseases. Dendritic cells (DCs) are the sentinels of the immune system that maintain immune tolerance through cytokines and regulatory T-cells generation. Aging disturbs the microbial composition of the gut, causing immune system dysregulation. However, the vis-à-vis role of gut dysbiosis on DCs tolerance remains highly elusive. Consequently, we studied the influence of aging on gut dysbiosis and its impact on the loss of DC tolerance. We show that DCs generated from either the aged (DCOld ) or gut-dysbiotic young (DCDysbiotic ) but not young (DCYoung ) mice exhibited loss of tolerance, as evidenced by their failure to optimally induce the generation of Tregs and control the overactivation of CD4+ T cells. The mechanism deciphered for the loss of DCOld and DCDysbiotic tolerance was chiefly through the overactivation of NF-κB, impaired frequency of Tregs, upregulation in the level of pro-inflammatory molecules (IL-6, IL-1β, TNF-α, IL-12, IFN-γ), and decline in the anti-inflammatory moieties (IL-10, TGF-β, IL-4, IDO, arginase, NO, IRF-4, IRF-8, PDL1, BTLA4, ALDH2). Importantly, a significant decline in the frequency of the Lactobacillus genus was noticed in the gut. Replenishing the gut of old mice with the Lactobacillus plantarum reinvigorated the tolerogenic function of DCs through the rewiring of inflammatory and metabolic pathways. Thus, for the first time, we demonstrate the impact of age-related gut dysbiosis on the loss of DC tolerance. This finding may open avenues for therapeutic intervention for treating age-associated disorders with the Lactobacillus plantarum.

| S-EPMC10265174 | biostudies-literature

The Gut Epithelial Receptor LRRC19 Promotes the Recruitment of Immune Cells and Gut Inflammation.

Project description:Commensal microbes are necessary for a healthy gut immune system. However, the mechanism involving these microbes that establish and maintain gut immune responses is largely unknown. Here, we have found that the gut immune receptor leucine-rich repeat (LRR) C19 is involved in host-microbiota interactions. LRRC19 deficiency not only impairs the gut immune system but also reduces inflammatory responses in gut tissues. We demonstrate that the LRRC19-associated chemokines CCL6, CCL9, CXCL9, and CXCL10 play a critical role in immune cell recruitment and intestinal inflammation. The expression of these chemokines is associated with regenerating islet-derived (REG) protein-mediated microbiotas. We also found that the expression of REGs may be regulated by gut Lactobacillus through LRRC19-mediated activation of NF-?B. Therefore, our study establishes a regulatory axis of LRRC19, REGs, altered microbiotas, and chemokines for the recruitment of immune cells and the regulation of intestinal inflammation.

| S-EPMC4742566 | biostudies-literature

Dispersal limitation promotes the diversification of the mammalian gut microbiota.

Project description:The gut bacterial communities of mammals have profound effects on host fitness, but the processes that generate and maintain gut bacterial diversity remain poorly understood. We mapped compositional variation (i.e., ?-diversity) in the gut microbiotas of 136 pairs of wild mammalian species living throughout the Americas to assess how the distribution of mammals across geographic space influences the diversification of their gut bacteria. Comparing the gut microbiotas of sympatric and allopatric mammalian populations provided insights into the flow of gut bacteria within and between mammalian communities, revealing that spatial limits on bacterial dispersal promote ?-diversity between the gut microbiotas of mammalian species. Each geographic locale displayed a unique gut-microbiota composition that could not be fully explained by the diets and phylogenetic histories of the resident mammalian hosts, indicating that some gut bacteria are geographically restricted. Across the western hemisphere, the compositional overlap between the gut microbiotas of allopatric mammalian populations decayed exponentially with the geographic distance separating the hosts. The relationship between geographic distances among hosts and compositional differences among their gut microbiotas was independent of dietary and phylogenetic divergence among hosts. Within mammalian communities, we observed widespread sharing of gut bacteria between predator-prey host-species pairs, indicating horizontal transfer of gut bacteria through mammalian food chains. Collectively, these results indicate that compositional differences between the gut microbiotas of mammalian taxa are generated and maintained by limits to bacterial dispersal imposed by physical distance between hosts.

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Metaproteomic Profiling of Functional Changes Driven by Gut Fungal Colonization

Project description:Gut microbiome modulates the host immune development, yet the functional contribution of gut fungi remains elusive. We previously showed that mice colonized only with fungi displayed allergic features and fecal metabolite profiles similar to germ-free mice. To gain insights into the functional changes attributed to fungal colonization, we performed proteomic analyses of feces and small intestine of gnotobiotic mice colonized with either bacteria, fungi, or both. Comparison of fecal metaproteomic profiles between mouse groups yielded broad changes in the relative levels of bacterial, fungal and mouse proteins. Many of the detected fungal proteins have been previously reported as a part of extracellular vesicles and having immunomodulating properties. Changes in the levels of mouse proteins derived from the small intestine impacted essential cellular pathways, including lipid metabolism and apoptosis. The results show how fungal colonization impacts the host proteome and suggest an influence on the host final cellular phenotype.

2022-02-28 | PXD019355 | Pride

CapA, an autotransporter protein of Campylobacter jejuni, mediates association with human epithelial cells and colonization of the chicken gut.

Project description:Two putative autotransporter proteins, CapA and CapB, were identified in silico from the genome sequence of Campylobacter jejuni NCTC11168. The genes encoding each protein contain homopolymeric tracts, suggestive of phase variation mediated by a slipped-strand mispairing mechanism; in each case the gene sequence contained frameshifts at these positions. The C-terminal two-thirds of the two genes, as well as a portion of the predicted signal peptides, were identical; the remaining N-terminal portions were gene specific. Both genes were cloned and expressed; recombinant polypeptides were purified and used to raise rabbit polyclonal monospecific antisera. Using immunoblotting, expression of the ca.116-kDa CapA protein was demonstrated for in vitro-grown cells of strain NCTC11168, for 4 out of 11 recent human fecal isolates, and for 2 out of 8 sequence-typed strains examined. Expression of CapB was not detected for any of the strains tested. Surface localization of CapA was demonstrated by subcellular fractionation and immunogold electron microscopy. Export of CapA was inhibited by globomycin, reinforcing the bioinformatic prediction that the protein is a lipoprotein. A capA insertion mutant had a significantly reduced capacity for association with and invasion of Caco-2 cells and failed to colonize and persist in chickens, indicating that CapA plays a role in host association and colonization by Campylobacter. In view of this demonstrated role, we propose that CapA stands for Campylobacter adhesion protein A.

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The Tumor Milieu Promotes Functional Human Tumor-Resident Plasmacytoid Dendritic Cells in Humanized Mouse Models.

Project description:Particular interest to harness the innate immune system for cancer immunotherapy is fueled by limitations of immune checkpoint blockade. Plasmacytoid dendritic cells (pDC) are detected in a variety of solid tumors and correlate with poor clinical outcome. Release of type I interferons in response to toll-like-receptor (TLR)7 and TLR9 activation is the pDC hallmark. Mouse and human pDC differ substantially in their biology concerning surface marker expression and cytokine production. Here, we employed humanized mouse models (HIS) to study pDC function. We performed a comprehensive characterization of transgenic, myeloid-enhanced mouse strains (NOG-EXL and NSG-SGM3) expressing human interleukin-3 (hIL-3) and granulocyte-macrophage colony stimulating factor (GM-CSF) using identical humanization protocols. Only in HIS-NOG-EXL mice sufficient pDC infiltration was detectable. Therefore, we selected this strain for subsequent tumor studies. We analyzed pDC frequency in peripheral blood and tumors by comparing HIS-NOG-EXL with HIS-NOG mice bearing three different ovarian and breast tumors. Despite the substantially increased pDC numbers in peripheral blood of HIS-NOG-EXL mice, we detected TLR7/8 agonist responsive and thus functional pDCs only in certain tumor models independent of the mouse strain employed. However, HIS-NOG-EXL mice showed in general a superior humanization phenotype characterized by reconstitution of different myeloid subsets, NK cells and B cells producing physiologic IgG levels. Hence, we provide first evidence that the tumor milieu but not genetically introduced cytokines defines intratumoral (i.t.) frequencies of the rare pDC subset. This study provides model systems to investigate in vivo pro- and anti-tumoral human pDC functions.

| S-EPMC7507800 | biostudies-literature

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