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 (PLCe), 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 PLCe participates in the psoriasis-like inflammation in PLCe overexpressing transgenic mice model, while the reduction in PLCe expression attenuates inflammatory responses in either TPA- or DNFB-induced cutaneous inflammation. Here, we determined the role of PLCe in cutaneous inflammation induced by acute abrogation of epidermal permeability barrier. In comparison to wild type controls, PLCe KO mice exhibited reduced ear swelling and infiltration of granulocytes after tape-stripping. Moreover, expression levels of pro-inflammatory cytokines (IL-1α, IL-1β), chemokines (CXCL-1, CXCL-2, CCL20), and antimicrobial peptides (S100 proteins, MBD3) were lower in PLCe-deficient versus wild type mice. Likewise, expression levels of cytokines and chemokines were also lower in PLCe deficient keratinocytes and fibroblasts following IL-22 stimulation in vitro. Furthermore, knockdown of PLCe with its siRNA decreased expression of IL-1α, CCL20, and S100 proteins, and MBD3 in HEK cultures. Collectively, these results suggested that PLCe mediated cytokine cascade induced by acute barrier disruption. IL-22 is likely the upstream of PLCe-mediated cytokine cascade following acute barrier disruption.