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Effect of Thrombin-Induced MCP-1 and MMP-3 Production Via PAR1 Expression in Murine Intervertebral Discs.

ABSTRACT: Structural changes in nucleus pulposus cells induce intervertebral disc (IVD) degeneration as a consequence of cytokine generation, biochemical products, and changes in the local environment. We have previously shown that inflammatory cytokines induce murine IVD (mIVD) angiogenesis and macrophage migration. Although the physiological roles of thrombin, a known proinflammatory factor, are documented, its relationship to IVD degeneration remains largely unexplored. Thrombin mediates cellular responses via the activation of protease-activated receptors such as PAR1 which has been studied in numerous cell types, but not extensively in IVD cells. This study was designed to investigate the endogenous expression of thrombin, tissue factor, and PAR1 in cultured coccygeal mIVDs. Thrombin exclusively induced MCP-1 via the MAPK-ERK and PI3K-AKT pathways. MCP-1 produced by mIVDs induced macrophage migration and thrombin treatment increased MMP-3 production to induce mIVD degeneration. These effects of thrombin on mIVDs were abrogated by a PAR1 inhibitor and suggest that thrombin may be a novel factor capable of stimulating cytokine activity implicated in the regulation several aspects of mIVDs. Mechanisms governing mIVDs, which are regulated by thrombin/PAR1 signaling, require elucidation if our understanding of IVD degenerative mechanisms is to advance.

SUBMITTER: Takayama Y

PROVIDER: S-EPMC6063965 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Essentials Elimination of PDAC tumor cell PAR1 increased cytotoxic T cells and reduced tumor macrophages. PAR1KO PDAC cells are preferentially eliminated from growing tumors. Thrombin-PAR1 signaling in PDAC tumor cells drives an immunosuppressive gene signature. Csf2 and Ptgs2 are thrombin-PAR1 downstream immune suppressor genes in PDAC tumor cells. ABSTRACT: Background Pancreatic ductal adenocarcinoma (PDAC) is characterized by a prothrombotic state and a lack of host antitumor immune responsiveness. Linking these two key features, we previously demonstrated that tumor-derived coagulation activity promotes immune evasion. Specifically, thrombin-protease-activated receptor-1 (PAR1) signaling in mouse PDAC cells drives tumor growth by evading cytotoxic CD8a+ cells. Methods Syngeneic mixed cell tumor growth, transcriptional analyses, and functional tests of immunosuppressive response genes were used to identify cellular and molecular immune evasion mechanisms mediated by thrombin-PAR-1 signaling in mouse PDAC tumor cells. Results Elimination of tumor cell PAR1 in syngeneic graft studies increased cytotoxic T lymphocyte (CTL) infiltration and decreased tumor-associated macrophages in the tumor microenvironment. Co-injection of PAR1-expressing and PAR1-knockout (PAR-1KO ) tumor cells into immunocompetent mice resulted in preferential elimination of PAR-1KO cells from developing tumors, suggesting that PAR1-dependent immune evasion is not reliant on CTL exclusion. Transcriptomics analyses revealed no PAR1-dependent changes in the expression of immune checkpoint proteins and no difference in major histocompatibility complex-I cell surface expression. Importantly, thrombin-PAR1 signaling in PDAC cells upregulated genes linked to immunosuppression, including Csf2 and Ptgs2. Functional analyses confirmed that both Csf2 and Ptgs2 are critical for PDAC syngeneic graft tumor growth and overexpression of each factor partially restored tumor growth of PAR1KO cells in immunocompetent mice. Conclusions Our results provide novel insight into the mechanisms of a previously unrecognized pathway coupling coagulation to PDAC immune evasion by identifying PAR1-dependent changes in the tumor microenvironment, a PAR1-driven immunosuppressive gene signature, and Csf2 and Ptgs2 as critical PAR1 downstream targets.

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Effect of Thrombin-Induced MCP-1 and MMP-3 Production Via PAR1 Expression in Murine Intervertebral Discs.

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