Lysophosphatidylcholine Facilitates The Pathogenesis Of Psoriasis Through Activating Glycolysis

Psoriasis is an immune-mediated chronic inflammatory disease characterized by recurrent skin lesions,including erythema,scales,and infiltration.Psoriasis seriously affects the physical and mental health of patients.The pathogenesis of psoriasis involves abnormal activation of keratinocytes(KCs)and imbalance of T cell function,such as Th1 and Th17 cells.Although abnormal metabolism plays a critical role in the pathogenesis of psoriasis,the details are unclear.Our previous study revealed that glycerophospholipid metabolism is majorly altered in psoriasis.Lysophosphatidylcholine(LPC)was significantly increased in psoriatic patient plasma according to lipidomics profiling.LPC induces inflammatory effects via various signaling pathways,but the role of LPC in psoriasis remains poorly understood.In this study,we intend to investigate the biological role of LPC on the pathogenesis of psoriasis.Lysophosphatidylcholine activates keratinocytes by regulating glycolysisObjective: To explore the role of LPC on the pathogenesis of psoriasis and on activating keratinocytes(KCs).Methods: 1)The level of LPC in the plasma of psoriasis patients was detected by enzyme-linked immunosorbent assay,and the level of LPC in the skin lesions of psoriasis patients was determined through liquid chromatography-tandem mass spectrometry.2)The glycolysis in the skin lesions of imiquimod(IMQ)-induced psoriasis-like mouse model was detected by extracellular acidification rate(ECAR).3)LPC was subcutaneously injected into IMQ-treated mouse ears,and the phenotype and the immune cell infiltration as well as the glycolysis were evaluated.4)To further understand the molecular mechanism of LPC,RNA sequencing(RNA-seq)was performed with skin lesions of the IMQinduced mouse model in the presence of the vehicle control or LPC.5)Exploring the role of LPC on KCs by culturing primary keratinocytes in vitro.Results: 1)LPC production was increased in plasma and skin lesions from psoriasis patients compared with that of healthy controls.2)The abundance of LPC was positively correlated with glycolytic activity in the psoriasis-like mouse model.3)LPC treatment dramatically facilitated psoriasis-like inflammation,epidermal thickness,immune cells(Th1,Th17,and γδT cells)infiltration,and glycolytic activity in skin lesions.4)RNA-seq analysis revealed that LPC activated glycolysis and the JAK-STAT signaling pathway;LPC elevated the expression of psoriasisassociated inflammatory factors,including Il6,Il17 a,Il1β,Il23 a,Cxcl1,Cxcl5,and S100a9,in LPC-induced skin lesions 5)LPC could not directly affect human primary KCs proliferation.However,LPC significantly triggered glycolytic activity and produced inflammatory factors(IL-1β and IL-17A)in keratinocytes in vitro.6)Mechanistically,LPC activated STAT1,resulting in recognition and binding to the promoters of GCK and PKLR,which are glycolytic ratelimiting enzymes.Conclusion: Our findings revealed the role of the LPC in the pathogenesis of psoriasis.LPC activates keratinocytes via enhancing glycolysis.Lysophosphatidylcholine promotes the CD4~+ T cells differentiation through regulating glycolysisObjective:To determine the effects of LPC on the proliferation and differentiation of CD4~+ T cells in vitro.Methods: 1)Mouse na(?)ve CD4~+ T cells were isolated and activated by anti-CD3 and anti-CD28 Abs upon LPC treatment.The proliferation of CD4~+ T cells was detected by CFSE staining.2)Then,we activated na(?)ve CD4~+ T cells under Th1-,Th17-,and Treg-polarizing conditions in vitro in the presence or absence of LPC.3)RNA sequencing(RNA-seq)was performed to understand the mechanism of LPC on the differentiation of CD4~+ T cells.4)The glycolysis of CD4~+ T cells was tested by ECAR.Results: 1)LPC had no effect on the proliferation of na(?)ve CD4~+ T cells in vitro.2)LPC remarkably facilitated CD4~+IFN-γ+ Th1 differentiation but did not affect Th17 or Tregs cells differentiation in vitro.3)RNA-seq analysis revealed that LPC activated glycolysis and the JAK-STAT signaling pathway in na(?)ve CD4~+ T cells under Th1-polarizing conditions.4)LPC promoted CD4~+IFN-γ+ Th1 differentiation through enhancing glycolysis.Blocking glycolysis abolished LPC-induced Th1 differentiation.5)LPC indirectly facilitated Th17 differentiation by inducing the secretion of IL-1β in keratinocytes-T cells coculture system.Conclusion: LPC promotes the differentiation of Th1 cells through increasing glycolysis and indirectly facilitates Th17 differentiation by inducing the secretion of IL-1β in keratinocytes.Lysophosphatidylcholine-facilitated the pathogenesis of psoriasis depends on G2 A expressionObjective:To explore the receptors dependent on LPC in the pathogenesis of psoriasis.Methods: 1)The location and expression of G2 A on the skin lesions of psoriasis were detected by immunohistochemistry.2)To investigate the role of G2 A in LPC-aggravated psoriasis-like pathological progression,we knocked down G2 A in the IMQ-induced psoriasis-like mouse model by injecting G2 A si RNA via the tail vein.3)To determine the role of G2 A in LPC-activated keratinocytes and LPC-promoted Th1 differentiation,we knocked down G2 A in the primary KCs and na(?)ve CD4~+ T cells by infecting G2 A sh RNA in vitro.Results: 1)G2A was highly expressed in psoriatic skin lesions,and G2 A expression was positively correlated with disease severity of psoriasis.2)The suppression of G2 A expression in mice abrogated the LPCaggravated psoriasis-like phenotype and epidermal thickness,LPCincreased infiltration of Th1,Th17,and γδT cells in skin lesions,and LPCpromoted expression of inflammatory factors(Il1β,Il17 a,Il6,and Il23a)in skin lesions of the IMQ-induced psoriasis-like mouse model.3)LPC failed to induce IL-1β and IL-17 A expression or glycolysis and glycolytic capacity in G2A-knockdown KCs.4)The suppression of G2 A expression abolished LPC-induced Th1 differentiationConclusion: The stimulatory effects of LPC on the development of psoriasis are G2A-dependent.58 figures,14 tables and 109 references...