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Critical Role for the Microbiota in CX₃CR1⁺ Intestinal Mononuclear Phagocyte Regulation of Intestinal T Cell Responses.

ABSTRACT: The intestinal barrier is vulnerable to damage by microbiota-induced inflammation that is normally restrained through mechanisms promoting homeostasis. Such disruptions contribute to autoimmune and inflammatory diseases including inflammatory bowel disease. We identified a regulatory loop whereby, in the presence of the normal microbiota, intestinal antigen-presenting cells (APCs) expressing the chemokine receptor CX₃CR1 reduced expansion of intestinal microbe-specific T helper 1 (Th1) cells and promoted generation of regulatory T cells responsive to food antigens and the microbiota itself. We identified that disruption of the microbiota resulted in CX₃CR1⁺ APC-dependent inflammatory Th1 cell responses with increased pathology after pathogen infection. Colonization with microbes that can adhere to the epithelium was able to compensate for intestinal microbiota loss, indicating that although microbial interactions with the epithelium can be pathogenic, they can also activate homeostatic regulatory mechanisms. Our results identify a cellular mechanism by which the microbiota limits intestinal inflammation and promotes tissue homeostasis.

SUBMITTER: Kim M

PROVIDER: S-EPMC6051886 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Natural killer (NK) cell can inhibit tumor initiation and regulates metastatic dissemination, acting as key mediators of the innate immune response. Intrinsic factors modulating NK cells infiltration and its anticancer activity remain poorly characterized. We investigated the roles of dysregulation of micro(mi)RNAs and NK cells in progression of hepatocellular carcinoma (HCC). Methods: Small RNA sequencing were used to detect the miRNA profiles of tumor tissues from HCC patients with (n=14) or without (n=13) pulmonary metastasis and HCC cell lines with different pulmonary metastatic potentials. Chemokine expression profiling and bioinformatics were used to detect the downstream target of candidate target. In gain- and loss-of-function assays were used to investigate the role of miRNA in HCC progression. Different subsets of NK cells were isolated and used for chemotaxis and functional assays in vivo and in vitro. In situ hybridization and immunohistochemical analyses were performed to detect the expression of miRNA in tumor tissues from 242 HCC patients undergoing curative resection from 2010. Results: Three miRNAs (miR-137, miR-149-5p, and miR-561-5p) were identified to be associated with pulmonary metastasis in patients with HCC. miR-561-5p was most highly overexpressed in metastatic HCC tissues and high-metastatic-potential HCC cell lines. In gain- and loss-of-function assays in a murine model, miR-561-5p promoted tumor growth and spread to the lungs. Yet, miR-561-5p did not appear to affect cellular proliferation and migration in vitro. Bioinformatics and chemokine expression profiling identified chemokine (C-X3-C motif) ligand 1 (CX3CL1) as a potential target of miR-561-5p. Furthermore, miR-561-5p promoted tumorigenesis and metastasis via CX3CL1-dependent regulation of CX3CR1+ NK cell infiltration and function. CX3CR1+ NK cells demonstrated stronger in vivo anti-metastatic activity relative to CX3CR1- NK cells. CX3CL1 stimulated chemotactic migration and cytotoxicity in CX3CR1+ NK cells via STAT3 signaling. Blockade of CX3CL1, CX3CR1, or of pSTAT3 signaling pathways attenuated the antitumor responses. Clinical samples exhibited a negative correlation between miR-561-5p expression and levels of CX3CL1 and CX3CR1+ NK cells. High miR-561-5p abundance, low CX3CL1 levels, and low numbers of CX3CR1+ NK cells were associated with adverse prognosis. Conclusion: We delineated a miR-561-5p/CX3CL1/NK cell axis that drives HCC metastasis and demonstrated that CX3CR1+ NK cells serve as potent antitumor therapeutic effectors.

Project description:A coordinated host immune response mediated via chemokine network plays a crucial role in boosting defense mechanisms against pathogenic infections. The speed of Ag presentation and delivery by CD11c+ dendritic cells (DCs) to cognate T cells in lymphoid tissues may decide the pathological severity of the infection. Here, we investigated the role of CX3CR1 in the neuroinflammation induced by infection with Japanese encephalitis virus (JEV), a neurotrophic virus. Interestingly, CX3CR1 deficiency strongly enhanced susceptibility to JEV only after peripheral inoculation via footpad. By contrast, both CX3CR1+/+ and CX3CR1-/- mice showed comparable susceptibility to JEV following inoculation via intranasal and intraperitoneal routes. CX3CR1-/- mice exhibited lethal neuroinflammation after JEV inoculation via footpad route, showing high mortality, morbidity, pro-inflammatory cytokine expression, and uncontrolled CNS-infiltration of peripheral leukocytes including Ly-6Chi monocytes and Ly-6Ghi granulocytes. Furthermore, the absence of CX3CR1+CD11c+ DCs appeared to enhance susceptibility of CX3CR1-/- mice to JE after peripheral JEV inoculation. CX3CR1 ablation impaired the migration of CX3CR1+CD11c+ DCs from JEV-inoculated sites to draining lymph nodes (dLNs), resulting in decreased NK cell activation and JEV-specific CD4+/CD8+ T-cell responses. However, CX3CR1-competent mice showed rapid temporal expression of viral Ags in dLNs. Subsequently, JEV was rapidly cleared, with concomitant generation of antiviral NK cell activation and T-cell responses mediated by rapid migration of JEV Ag+CX3CR1+CD11c+ DCs. Using biallelic functional CX3CR1 expression system, the functional expression of CX3CR1 on CD11chi DCs appeared to be essentially required for inducing rapid and effective responses of NK cell activation and Ag-specific CD4+ T cells in dLNs. Strikingly, adoptive transfer of CX3CR1+CD11c+ DCs was found to completely restore the resistance of CX3CR1-/- recipients to JEV, as corroborated by the rapid delivery of JEV Ags in dLNs and attenuation of neuroinflammation in the CNS. Collectively, these results indicate that CX3CR1+CD11c+ DCs play an important role in generating rapid and effective responses of antiviral NK cell activation and Ag-specific T cells after peripheral inoculation with the virus, thereby resulting in conferring resistance to viral infection by reducing the peripheral viral burden.

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Critical Role for the Microbiota in CX₃CR1⁺ Intestinal Mononuclear Phagocyte Regulation of Intestinal T Cell Responses.

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Critical Role for the Microbiota in CX3CR1+ Intestinal Mononuclear Phagocyte Regulation of Intestinal T Cell Responses.

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Critical Role for the Microbiota in CX₃CR1⁺ Intestinal Mononuclear Phagocyte Regulation of Intestinal T Cell Responses.