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Lysophosphatidic Acid Receptor 5 Contributes to Imiquimod-Induced Psoriasis-Like Lesions through NLRP3 Inflammasome Activation in Macrophages.

ABSTRACT: The pathogenesis of psoriasis, an immune-mediated chronic skin barrier disease, is not fully understood yet. Here, we identified lysophosphatidic acid (LPA) receptor 5 (LPA5)-mediated signaling as a novel pathogenic factor in psoriasis using an imiquimod-induced psoriasis mouse model. Amounts of most LPA species were markedly elevated in injured skin of psoriasis mice, along with LPA5 upregulation in injured skin. Suppressing the activity of LPA5 with TCLPA5, a selective LPA5 antagonist, improved psoriasis symptoms, including ear thickening, skin erythema, and skin scaling in imiquimod-challenged mice. TCLPA5 administration attenuated dermal infiltration of macrophages that were found as the major cell type for LPA5 upregulation in psoriasis lesions. Notably, TCLPA5 administration attenuated the upregulation of macrophage NLRP3 in injured skin of mice with imiquimod-induced psoriasis. This critical role of LPA5 in macrophage NLRP3 was further addressed using lipopolysaccharide-primed bone marrow-derived macrophages. LPA exposure activated NLRP3 inflammasome in lipopolysaccharide-primed cells, which was evidenced by NLRP3 upregulation, caspase-1 activation, and IL-1? maturation/secretion. This LPA-driven NLRP3 inflammasome activation in lipopolysaccharide-primed cells was significantly attenuated upon LPA5 knockdown. Overall, our findings establish a pathogenic role of LPA5 in psoriasis along with an underlying mechanism, further suggesting LPA5 antagonism as a potential strategy to treat psoriasis.

SUBMITTER: Gaire BP

PROVIDER: S-EPMC7465035 | biostudies-literature | 2020 Jul

REPOSITORIES: biostudies-literature

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Lysophosphatidic Acid Receptor 5 Contributes to Imiquimod-Induced Psoriasis-Like Lesions through NLRP3 Inflammasome Activation in Macrophages.

Gaire Bhakta Prasad BP Lee Chi-Ho CH Kim Wondong W Sapkota Arjun A Lee Do Yup DY Choi Ji Woong JW

Cells 20200722 8

The pathogenesis of psoriasis, an immune-mediated chronic skin barrier disease, is not fully understood yet. Here, we identified lysophosphatidic acid (LPA) receptor 5 (LPA5)-mediated signaling as a novel pathogenic factor in psoriasis using an imiquimod-induced psoriasis mouse model. Amounts of most LPA species were markedly elevated in injured skin of psoriasis mice, along with LPA5 upregulation in injured skin. Suppressing the activity of LPA5 with TCLPA5, a s ...[more]

PMID: 32707926

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Project description:BackgroundListeria monocytogenes (LM), a foodborne pathogen, can cause pregnancy failure in animals, especially in ruminants. Recent studies have shown that LM activates inflammasomes to induce IL-1β release in macrophages, however, whether the inflammasome activation regulates LM-induced pregnancy failure remains largely unknown. Here we used mouse model to investigate the molecular mechanism by which LM-induced inflammsome activation contributes to LM-associated pregnancy failureResultsWe showed that wild-type, but not Listeriolysin O-deficient (Δhly) LM, significantly reduced mouse embryo survival, accompanied by the increase of IL-1β release and caspase-1 activation. IL-1β neutralization significantly reduced the LM-induced embryo losses, suggesting that LM-induced pregnancy failure was associated with LLO-induced inflammasome activation. To dissect the inflammasome sensor and components responsible for LM-induced caspase-1 activation and IL-1β production, we used wild-type and NLRP3(-/-), AIM2(-/-), NLRC4(-/-), ASC(-/-), caspase-1(-/-) and cathepsin B(-/-) mouse macrophages to test the roles of these molecules in LM-induce IL-1β production. We found that NLRP3 inflammasome was the main pathway in LM-induced caspase-1 activation and IL-1β production. To explore the mechanism of LM-induced pregnancy failure, we investigated the effects of LM-infected macrophages on SM9-1 mouse trophoblasts. We found that the conditioned medium from LM-infected-macrophage or the recombinant IL-1β significantly up-regulated TNFα, IL-6 and IL-8 productions in trophoblasts, suggesting that the LM-induced macrophage inflammasome activation increased trophoblast pro-inflammatory cytokine production, which was adverse to the animal pregnancy maintenance.ConclusionsOur data demonstrated that the LLO-induced NLRP3 inflammasome activation plays a key role in LM-induced pregnancy failure, and inflammasome-mediated macrophage dysregulation on trophoblasts might be involved in the pregnancy failure.

Dataset Information

Lysophosphatidic Acid Receptor 5 Contributes to Imiquimod-Induced Psoriasis-Like Lesions through NLRP3 Inflammasome Activation in Macrophages.

Publications

Lysophosphatidic Acid Receptor 5 Contributes to Imiquimod-Induced Psoriasis-Like Lesions through NLRP3 Inflammasome Activation in Macrophages.

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