Lysophosphatidic Acid Receptor 5 Contributes to Imiquimod-Induced Psoriasis-Like Lesions through NLRP3 Inflammasome Activation in Macrophages.
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-1β 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.
['Gaire|Bhakta Prasad|BP|', 'Lee|Chi-Ho|CH|', 'Kim|Wondong|W|', 'Sapkota|Arjun|A|', 'Lee|Do Yup|DY|', 'Choi|Ji Woong|JW|']
D000818:Animals D001854:Bone Marrow Cells D002478:Cells, Cultured D004195:Disease Models, Animal D055785:Gene Knockdown Techniques D000077271:Imiquimod D058847:Inflammasomes D008070:Lipopolysaccharides D008264:Macrophages D008297:Male D051379:Mice D008807:Mice, Inbred BALB C D008813:Mice, Inbred ICR D000071199:NLR Family, Pyrin Domain-Containing 3 Protein D011565:Psoriasis D049368:Receptors, Lysophosphatidic Acid D015398:Signal Transduction D012867:Skin D014162:Transfection D015854:Up-Regulation
lysophosphatidic acid receptor 5 NLRP3 inflammasome macrophages psoriasis TCLPA5