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Pathogenic Roles of CXCL10 in Experimental Autoimmune Prostatitis by Modulating Macrophage Chemotaxis and Cytokine Secretion

ABSTRACT: Chronic prostatitis and chronic pelvic pain syndrome (CP/CPPS) is an inflammatory immune disease characterized by intraprostatic leukocyte infiltration and pelvic or perineal pain. Macrophages play vital roles in the pathogenesis of CP/CPPS. However, the mechanisms controlling the activation and chemotaxis of macrophages in CP/CPPS remain unclear. This study aimed to investigate the roles of the CXCL10/CXCR3 pathway in the activation and chemotaxis of macrophages in CP/CPPS patients. The serums of CP/CPPS patients and healthy volunteers were collected and measured. Results showed that CXCL10 expression was significantly elevated and correlated with the severity of CP/CPPS patients. The experimental autoimmune prostatitis (EAP) model was generated, and adeno-associated virus and CXCR3 inhibitors were used to treat EAP mice. Immunofluorescence, flow cytometry, and Western blotting were used to analyze the functional phenotype and regulation mechanism of macrophages. Results showed that CXCL10 deficiency ameliorates EAP severity by inhibiting infiltration of macrophages to prostate. Moreover, CXCL10 could induce macrophage migrations and secretions of proinflammatory mediators via CXCR3, which consequently activated the downstream Erk1/2 and p38 MAPK signaling pathways. We also showed that prostatic stromal cell is a potential source of CXCL10. Our results indicated CXCL10 as an important mediator involved in inflammatory infiltration and pain symptoms of prostatitis by promoting the migration of macrophages and secretion of inflammatory mediators via CXCR3-mediated ERK and p38 MAPK activation.

SUBMITTER: Hua X

PROVIDER: S-EPMC8511489 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Rheumatoid arthritis (RA) is a chronic autoimmune disease characterized by uncontrolled joint inflammation and destruction of bone and cartilage. We previously reported that C-X-C motif chemokine 10 (CXCL10; also called IP-10) has important roles in joint inflammation and bone destruction in arthritis. However, the specific mechanisms by which CXCL10 regulates the recruitment of inflammatory cells and the production of osteoclastogenic cytokines in RA progression are not fully understood.Bone marrow-derived macrophages and CD4+ T cells were isolated from wild-type (WT), Cxcl10 -/-, and Cxcr3 -/- mice. CXCL10-induced migration was performed using a Boyden chamber, and CXCL10-stimulated production of osteoclastogenic cytokines was measured by quantitative real-time PCR and ELISA. Collagen antibody-induced arthritis (CAIA) was induced by administration of collagen type II antibodies and lipopolysaccharide to the mice. Clinical scores were analyzed and hind paws were collected for high-resolution micro-CT, and histomorphometry. Serum was used to assess bone turnover and levels of osteoclastogenic cytokines.CXCL10 increased the migration of inflammatory cells through C-X-C chemokine receptor 3 (CXCR3)-mediated, but not toll-like receptor 4 (TLR4)-mediated, ERK activation. Interestingly, both receptors CXCR3 and TLR4 were simultaneously required for CXCL10-stimulated production of osteoclastogenic cytokines in CD4+ T cells. Furthermore, calcineurin-dependent NFATc1 activation was essential for CXCL10-induced RANKL expression. In vivo, F4/80+ macrophages and CD4+ T cells robustly infiltrated into synovium of WT mice with CAIA but were significantly reduced in both Cxcl10 -/- and Cxcr3 -/- mice. Serum concentrations of osteoclastogenic cytokines and bone destruction were also reduced in the knockout mice, leading to attenuated progression of arthritis.These findings highlight the importance of CXCL10 signaling in the pathogenesis of RA and provide previously unidentified details of the mechanisms by which CXCL10 promotes the development of arthritis.

Project description:BackgroundInflammation is a key hallmark of ALI and is mediated through ungoverned cytokine signaling. One such cytokine, interleukin-1beta (IL-1β) has been demonstrated to be the most bioactive cytokine in ALI patients. Macrophages are the key players responsible for IL-1β secretion into the alveolar space. Following the binding of IL-1β to its receptor, "activated" alveolar epithelial cells show enhanced barrier dysfunction, adhesion molecule expression, cytokine secretion, and leukocyte attachment. More importantly, it is an important communication molecule between the macrophage and alveolar epithelium. While the molecular determinants of this inflammatory event have been well documented, endogenous resolution processes that decrease IL-1β secretion and resolve alveolar epithelial cell activation and tissue inflammation have not been well characterized. Lipid mediator Aspirin-Triggered Resolvin D1 (AT-RvD1) has demonstrated potent pro-resolutionary effects in vivo models of lung injury; however, the contribution of the alveoli to the protective benefits of this molecule has not been well documented. In this study, we demonstrate that AT-RvD1 treatment lead to a significant decrease in oxidant induced macrophage IL-1β secretion and production, IL-1β-mediated cytokine secretion, adhesion molecule expression, leukocyte adhesion and inflammatory signaling.MethodsTHP-1 macrophages were treated with hydrogen peroxide and extracellular ATP in the presence or absence of AT-RvD1 (1000-0.1 nM). A549 alveolar-like epithelial cells were treated with IL-1β (10 ng/mL) in the presence or absence of AT-RvD1 (0.1 μM). Following treatment, cell lysate and cell culture supernatants were collected for Western blot, qPCR and ELISA analysis of pro-inflammatory molecules. Functional consequences of IL-1β induced alveolar epithelial cell and macrophage activation were also measured following treatment with IL-1β ± AT-RvD1.ResultsResults demonstrate that macrophages exposed to H2O2 and ATP in the presence of resolvins show decreased IL-1β production and activity. A549 cells treated with IL-1β in the presence of AT-RvD1 show a reduced level of proinflammatory cytokines IL-6 and IL-8. Further, IL-1β-mediated adhesion molecule expression was also reduced with AT-RvD1 treatment, which was correlated with decreased leukocyte adhesion. AT-RvD1 treatment demonstrated reduced MAP-Kinase signaling. Taken together, our results demonstrate AT-RvD1 treatment reduced IL-1β-mediated alveolar epithelial cell activation. This is a key step in unraveling the protective effects of resolvins, especially AT-RvD1, during injury.

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Pathogenic Roles of CXCL10 in Experimental Autoimmune Prostatitis by Modulating Macrophage Chemotaxis and Cytokine Secretion

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