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Probiotics Prevent Hypertension in a Murine Model of Systemic Lupus Erythematosus Induced by Toll-Like Receptor 7 Activation.

ABSTRACT: Our group tested the effects of Lactobacillus fermentum CECT5716 (LC40) and/or Bifidobacterium breve CECT7263 (BFM) in the prevention of gut dysbiosis, hypertension and endothelial dysfunction in a pharmacologically-induced model of systemic lupus erythematosus (SLE). We treated eight-week-old BALB/cByJRj mice without (Ctrl) or with the agonist of TLR-7 Imiquimod (IMQ) for 8 weeks. Concomitantly, LC40 (10⁹ CFU/mL) and BFM (10⁹ CFU/mL) were administered through oral gavage once a day. IMQ induced intestinal dysbiosis consisting of a decrease in the α-diversity measured with Chao-richness and numbers of species. LC40 and BFM did not restore these parameters. The three-dimensional principal component analysis of bacterial taxa in stool samples presented perfect clustering between Ctrl and IMQ groups. Clusters corresponding to LC40 and BFM were more akin to IMQ. BFM and LC40 were detected colonizing the gut microbiota of mice treated respectively. LC40 and BFM decreased plasma double-stranded DNA autoantibodies, and B cells in spleen, which were increased in the IMQ group. Also, LC40 and BFM treatments activated TLR9, reduced T cells activation, and Th17 polarization in mesenteric lymph nodes. Aortae from IMQ mice displayed a decreased endothelium-dependent vasodilator response to acetylcholine linked to pro-inflammatory and pro-oxidative status, which were normalized by both BFM and LC40. In conclusion, we demonstrate for the first time that the chronic treatment with LC40 or BFM prevented hypertension and endothelial dysfunction in a mouse lupus model induced by TLR-7 activation.

SUBMITTER: de la Visitacion N

PROVIDER: S-EPMC8399640 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Background: Activation of Toll-like receptors (TLRs) induces inflammatory responses involved in immunity to pathogens and autoimmune pathogenesis, such as in patients with systemic lupus erythematosus (SLE). Although TLRs are differentially expressed across the immune system, a comprehensive analysis of how multiple immune cell subsets respond in a system-wide manner has not been described.Objective: We sought to characterize TLR activation across multiple immune cell subsets and subjects, with the goal of establishing a reference framework against which to compare pathologic processes.Methods: Peripheral whole-blood samples were stimulated with TLR ligands and analyzed by means of mass cytometry simultaneously for surface marker expression, activation states of intracellular signaling proteins, and cytokine production. We developed a novel data visualization tool to provide an integrated view of TLR signaling networks with single-cell resolution. We studied 17 healthy volunteer donors and 8 patients with newly diagnosed and untreated SLE.Results: Our data revealed the diversity of TLR-induced responses within cell types, with TLR ligand specificity. Subsets of natural killer cells and T cells selectively induced nuclear factor κ light chain enhancer of activated B cells in response to TLR2 ligands. CD14(hi) monocytes exhibited the most polyfunctional cytokine expression patterns, with more than 80 distinct cytokine combinations. Monocytic TLR-induced cytokine patterns were shared among a group of healthy donors, with minimal intraindividual and interindividual variability. Furthermore, autoimmune disease altered baseline cytokine production; newly diagnosed untreated SLE patients shared a distinct monocytic chemokine signature, despite clinical heterogeneity.Conclusion: Mass cytometry defined a systems-level reference framework for human TLR activation, which can be applied to study perturbations in patients with inflammatory diseases, such as SLE.

Project description:To define the pathogenesis of bone marrow (BM) involvement in systemic lupus erythematosus (SLE).Tumor necrosis factor ? (TNF?) levels, cell death, and cellular damage in BM from SLE patients, controls, and mice with pristane-induced lupus were analyzed using a morphometric technique and immunohistochemistry. The pathogenesis of BM abnormalities was studied in wild-type (WT), TNF?(-/-) , Toll-like receptor-deficient (TLR-7(-/-) ), interferon (IFN)-?/?/? receptor-knockout (IFNAR(-/-) ), and B cell-deficient (?mt) mice treated with pristane. Flow cytometry was used to examine TNF? production (by intracellular staining) and plasma cell/plasmablast development. CXCL12 expression was determined by quantitative polymerase chain reaction.BM from SLE patients exhibited striking death of niche and hematopoietic cells associated with TNF? overproduction. BM from mice with a type I IFN-mediated lupus syndrome induced by pristane showed similar abnormalities. TNF? was produced mainly by BM neutrophils, many with phagocytosed nuclear material (lupus erythematosus cells). TNF? production was abolished in pristane-treated TLR-7(-/-) and ?mt mice but was restored in ?mt mice by infusing normal plasma. Pristane-treated WT and IFNAR(-/-) mice developed anemia, BM hypocellularity, and extramedullary hematopoiesis, which were absent in TLR-7(-/-) and TNF?(-/-) mice. Additionally, the expression of CXCL12, which is produced by stromal cells and mediates homing of hematopoietic cells and plasmablasts, was decreased in BM from pristane-treated WT mice but was normal in BM from pristane-treated TNF?(-/-) mice.Although autoantibodies and glomerulonephritis are type I IFN dependent, lupus-associated BM abnormalities were TLR-7 and TNF? driven but type I IFN independent, suggesting that lupus is a disorder of innate immunity in which TLR-7 activation by phagocytosed nuclei causes relentless type I IFN and TNF? production mediating glomerulonephritis and hematologic involvement, respectively.

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Probiotics Prevent Hypertension in a Murine Model of Systemic Lupus Erythematosus Induced by Toll-Like Receptor 7 Activation.

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