HIV induces production of IL-18 from intestinal epithelial cells that increases intestinal permeability and microbial translocation

Allam, Ossama; Samarani, Suzanne; Mehraj, Vikram; Jenabian, Mohammad-Ali; Tremblay, Cécile; Routy, Jean‐Pierre; Amre, Devendra; Ahmad, Ali

doi:10.1371/journal.pone.0194185

Cited by 32 publications

(24 citation statements)

References 87 publications

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“…To our knowledge, this is the first study that investigate gut inflammation through cytokine levels with a noninvasive approach in HIV+ patients. Other groups have already reported high levels of IL-18, IL-1β, and IL-8 in gut biopsies from HIV+ patients; in this study, it was proposed that the IL-18 production is induced on intestinal epithelial cells by HIV which promotes intestinal permeability and microbial translocation [42]. Even though our result are similar to this research, this highlights the importance of measuring this biomarker at different anatomical compartments [7].…”

Section: Discussionsupporting

confidence: 82%

Association of intestinal and systemic inflammatory biomarkers with immune reconstitution in HIV+ patients on ART

et al. 2020

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Background HIV infection is characterized by CD4+ T-cells depletion related to gut damage, microbial translocation, immune activation and intestinal and systemic low-grade inflammation. With the use of antiretroviral treatment, these alterations in HIV+ patients reach similar levels to HIV- controls. However, almost 20% patients have deficient immune reconstitution of CD4+ T-cells, which make them more susceptible to develop non-AIDS and AIDS comorbidities. Methods HIV+ patients on ART, with sustained virologic control were grouped according to their immune reconstitution as: immunological responders (n = 18) and immunological non-responders (n = 18); also, HIV- controls were enrolled (n = 14). CD4+ and CD8+ T-cell activation (HLA-DR+ and CD38+ single and co-expression) were measured by flow cytometry. Serum levels of sCD14, sCD163, lipopolysaccharide, I-FABP, sST2, as well as fecal levels of calprotectin, lactoferrin and secretory IgA were evaluated by ELISA. Levels of C-reactive protein were determined by a high sensibility singleplex bead-based immunoassay. Serum and fecal concentrations of proinflammatory cytokines were quantified by multiplex bead-based immunoassay. Results HLA-DR+ and CD38+ co-expression, as well as median fluorescence intensity in CD4+ and CD8+ T-cells subpopulations was greater in immunological non-responders group, after normalization and fold change calculation. Similarly, this group presented higher levels of sCD14, C-reactive protein, as well as fecal calprotectin and lactoferrin. Furthermore, both HIV+ groups showed elevated levels of proinflammatory cytokines in stool. Conclusions Our data suggests that despite the virologic control, HIV+ patients under treatment with deficient immune reconstitution showed elevation of both innate and T-cells immune activation, as well as intestinal and systemic inflammation. However, some patients with CD4+ T-cells count above 350 cells/μL also presented these alterations. Future studies are necessary to evaluate the dynamics of multiple systemic and intestinal biomarkers in diverse types of HIV+ patients, as such as their clinical impact.

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Section: Discussionsupporting

confidence: 82%

Association of intestinal and systemic inflammatory biomarkers with immune reconstitution in HIV+ patients on ART

et al. 2020

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“…The inflammasome IL-1 and IL-18 cytokines could play an important role in orientating the mucosal immune response [28][29][30]. IL-18 seems predominant in the setting of HIV-1 infection [16,17]. We found increased plasma levels of IL-18, but not of IL-1, in the treated HIV-1-infected individuals included in the present study.…”

Section: Discussionsupporting

confidence: 45%

Increased CXCR3+ T Cells Impairs Recruitment of T-Helper Type 17 Cells via Interferon γ and Interleukin 18 in the Small Intestine Mucosa During Treated HIV-1 Infection

Loiseau

Requena²,

Nayrac

et al. 2019

The Journal of Infectious Diseases

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The restoration of CD4+ T cells, especially T-helper type 17 (Th17) cells, remains incomplete in the gut mucosa of most human immunodeficiency virus type 1 (HIV-1)–infected individuals despite sustained antiretroviral therapy (ART). Herein, we report an increase in the absolute number of CXCR3+ T cells in the duodenal mucosa during ART. The frequencies of Th1 and CXCR3+ CD8+ T cells were increased and negatively correlated with CCL20 and CCL25 expression in the mucosa. In ex vivo analyses, we showed that interferon γ, the main cytokine produced by Th1 and effector CD8+ T cells, downregulates the expression of CCL20 and CCL25 by small intestine enterocytes, while it increases the expression of CXCL9/10/11, the ligands of CXCR3. Interleukin 18, a pro-Th1 cytokine produced by enterocytes, also contributes to the downregulation of CCL20 expression and increases interferon γ production by Th1 cells. This could perpetuate an amplification loop for CXCR3-driven Th1 and effector CD8+ T cells recruitment to the gut, while impairing Th17 cells homing through the CCR6-CCL20 axis in treated HIV-1–infected individuals.

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“…57,58 IL-18 also increases gut permeability through decreasing the expression of tight junction proteins or occludin phosphorylation. 59,60 These results support the notion that increased numbers of mast cells and an increased degree of mast cell activation are linked to enhance intestinal permeability in individuals with IBS. Consistent with these findings, we found that MS increased the number of mast cells and activated mast cells to release tryptase.…”

Section: Discussionsupporting

confidence: 76%

“…Treatment with anti‐IL‐6 antibody counteracts increased gut permeability and alleviates IBS‐like symptoms . IL‐18 also increases gut permeability through decreasing the expression of tight junction proteins or occludin phosphorylation . These results support the notion that increased numbers of mast cells and an increased degree of mast cell activation are linked to enhance intestinal permeability in individuals with IBS.…”

Section: Discussionsupporting

confidence: 67%

Metformin prevents colonic barrier dysfunction by inhibiting mast cell activation in maternal separation‐induced IBS‐like rats

Yang

Yao

et al. 2019

Neurogastroenterology Motil

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Background Intestinal barrier dysfunction is a key etiologic factor of irritable bowel syndrome (IBS). Metformin improves intestinal barrier function, although the underlying mechanism has yet to be fully explained. This study evaluates the protective effect of metformin on colonic barrier integrity and explores the underlying cellular mechanisms. Methods IBS‐like rats were induced by maternal separation. Metformin was administered daily by gavage at 08:30, and rat pups were then separated from their mother. Visceral hyperalgesia and depression‐like behaviors were evaluated by colorectal distension, sucrose preference tests, and forced swimming tests. Intestinal integrity was analyzed using sugar probes and transmission electron microscopy. Inflammatory factors and the levels of corticotropin‐releasing factor were assessed by PCR and ELISA. The number of mast cells was evaluated by toluidine blue staining. Protein expression and localization were determined using Western blot and immunochemistry. Key Results Metformin pretreatment (a) reduced visceral hypersensitivity to colorectal distension, immobility time and enhanced sucrose consumption; (b) decreased urine lactulose/mannitol ratio and sucralose output; (c) inhibited the dilation of tight junction and prevented claudin‐4 translocation; (d) inhibited mast cell activation and downregulated the expression of IL‐6, IL‐18, tryptase, PAR‐2, and ERK activation; (e) inhibited claudin‐4 phosphorylation at serine sites and interactions between clau‐4 and ZO‐1. Conclusions & Inferences Metformin may block mast cell activation to reduce PAR‐2 expression and subsequently inhibit ERK activation and clau‐4 phosphorylation at serine sites to normalize the interaction of clau‐4 and ZO‐1 and clau‐4 distribution. Metformin may be clinically beneficial for patients with IBS or IBS‐like symptoms.

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HIV induces production of IL-18 from intestinal epithelial cells that increases intestinal permeability and microbial translocation

Cited by 32 publications

References 87 publications

Association of intestinal and systemic inflammatory biomarkers with immune reconstitution in HIV+ patients on ART

Association of intestinal and systemic inflammatory biomarkers with immune reconstitution in HIV+ patients on ART

Increased CXCR3+ T Cells Impairs Recruitment of T-Helper Type 17 Cells via Interferon γ and Interleukin 18 in the Small Intestine Mucosa During Treated HIV-1 Infection

Metformin prevents colonic barrier dysfunction by inhibiting mast cell activation in maternal separation‐induced IBS‐like rats

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