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Phospholipase C epsilon mediates cytokine cascade induced by acute disruption of epidermal permeability barrier in mice.

ABSTRACT: Disruption of epidermal barrier is an important trigger in abnormal cutaneous inflammation. Phospholipase C epsilon (PLC?), a Ras/Rap1 effector, is essential for regulating cytokines production in different types of skin inflammation. Our previous studies have demonstrated that elevated expression of PLC? participates in the psoriasis-like inflammation in PLC? overexpressing transgenic mice model, while the reduction in PLC? expression attenuates inflammatory responses in either TPA- or DNFB-induced cutaneous inflammation. Here, we determined the role of PLC? in cutaneous inflammation induced by acute abrogation of epidermal permeability barrier. In comparison to wild type controls, PLC? KO mice exhibited reduced ear swelling and infiltration of granulocytes after tape-stripping. Moreover, expression levels of pro-inflammatory cytokines (IL-1?, IL-1?), chemokines (CXCL-1, CXCL-2, CCL20), and antimicrobial peptides (S100 proteins, MBD3) were lower in PLC?-deficient versus wild type mice. Likewise, expression levels of cytokines and chemokines were also lower in PLC? deficient keratinocytes and fibroblasts following IL-22 stimulation in vitro. Furthermore, knockdown of PLC? with its siRNA decreased expression of IL-1?, CCL20, and S100 proteins, and MBD3 in HEK cultures. Collectively, these results suggested that PLC? mediated cytokine cascade induced by acute barrier disruption. IL-22 is likely the upstream of PLC?-mediated cytokine cascade following acute barrier disruption.

SUBMITTER: Zhang J

PROVIDER: S-EPMC7733008 | biostudies-literature | 2020 Dec

REPOSITORIES: biostudies-literature

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Phospholipase C epsilon mediates cytokine cascade induced by acute disruption of epidermal permeability barrier in mice.

Zhang Jing J Wu Jiangmei J Sun Mengke M Zhang Shuchang S Huang Junkai J Man Maoqiang M Hu Lizhi L

Biochemistry and biophysics reports 20201209

Disruption of epidermal barrier is an important trigger in abnormal cutaneous inflammation. Phospholipase C epsilon (PLCε), a Ras/Rap1 effector, is essential for regulating cytokines production in different types of skin inflammation. Our previous studies have demonstrated that elevated expression of PLCε participates in the psoriasis-like inflammation in PLCε overexpressing transgenic mice model, while the reduction in PLCε expression attenuates inflammatory responses in either TPA- or DNFB-ind ...[more]

PMID: 33336085

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Project description:BackgroundAlcoholic liver disease (ALD) is commonly associated with intestinal permeability. An unanswered question is why only a subset of heavy alcohol drinkers develop endotoxemia. Recent studies suggest that circadian disruption is the susceptibility factor for alcohol-induced gut leakiness to endotoxins. The circadian protein PER2 is increased after exposure to alcohol and siRNA knockdown of PER2 in vitro blocks alcohol-induced intestinal barrier dysfunction. We have shown that blocking CYP2E1 (i.e., important for alcohol metabolism) with siRNA inhibits the alcohol-induced increase in PER2 and suggesting that oxidative stress may mediate alcohol-induced increase in PER2 in intestinal epithelial cells. The aim of this study was to elucidate whether a mechanism incited by alcohol-derived oxidative stress mediates the transcriptional induction of PER2 and subsequent intestinal hyperpermeability.MethodsCaco-2 cells were exposed to 0.2% alcohol with or without pretreatment with modulators of oxidative stress or PKA activity. Permeability of the Caco-2 monolayer was assessed by transepithelial electrical resistance. Protein expression was measured by Western blot and mRNA with real-time polymerase chain reaction. Wild-type C57BL/6J mice were fed with alcohol diet (29% of total calories, 4.5% v/v) for 8 weeks. Western blot was used to analyze PER2 expression in mouse proximal colon tissue.ResultsAlcohol increased oxidative stress, caused Caco-2 cell monolayer dysfunction, and increased levels of the circadian clock proteins PER2 and CLOCK. These effects were mitigated by pretreatment of Caco-2 cells with an antioxidant scavenger. Alcohol-derived oxidative stress activated cAMP response element-binding (CREB) via the PKA pathway and increased PER2 mRNA and protein. Inhibiting CREB prevented the increase in PER2 and Caco-2 cell monolayer hyperpermeability.ConclusionsTaken together, these data suggest that strategies to reduce alcohol-induced oxidative stress may alleviate alcohol-mediated circadian disruption and intestinal leakiness, critical drivers of ALD.

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Phospholipase C epsilon mediates cytokine cascade induced by acute disruption of epidermal permeability barrier in mice.

Publications

Phospholipase C epsilon mediates cytokine cascade induced by acute disruption of epidermal permeability barrier in mice.

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