Formylpeptide receptor 1 contributes to epidermal barrier dysfunction-induced skin inflammation through NOD-like receptor C4-dependent keratinocyte activation

Background Skin barrier dysfunction may both initiate and aggravate skin inflammation. However, the mechanisms involved in the inflammation process remain largely unknown.Objectives We sought to determine how skin barrier dysfunction enhances skin inflammation and molecular mechanisms.Methods Skin barrier defect mice were established by tape stripping or topical use of acetone on wildtype mice, or filaggrin deficiency. RNA-Seq was employed to analyse the differentially expressed genes in mice with skin barrier defects. Primary human keratinocytes were transfected with formylpeptide receptor (FPR)1 or protein kinase R-like endoplasmic reticulum (ER) kinase (PERK) small interfering RNA to examine the effects of these gene targets. The expressions of inflammasome NOD-like receptor (NLR)C4, epidermal barrier genes and inflammatory mediators were evaluated.Results Mechanical (tape stripping), chemical (acetone) or genetic (filaggrin deficiency) barrier disruption in mice amplified the expression of proinflammatory genes, with transcriptomic profiling revealing overexpression of formylpeptide receptor (Fpr1) in the epidermis. Treatment with the FPR1 agonist fMLP in keratinocytes upregulated the expression of the NLRC4 inflammasome and increased interleukin-1 beta secretion through modulation of ER stress via the PERK-eIF2 alpha-C/EBP homologous protein pathway. The activation of the FPR1-NLRC4 axis was also observed in skin specimens from old healthy individuals with skin barrier defect or elderly mice. Conversely, topical administration with a FPR1 antagonist, or Nlrc4 silencing, led to the normalization of barrier dysfunction and alleviation of inflammatory skin responses in vivo.Conclusions In summary, our findings show that the FPR1-NLRC4 inflammasome axis is activated upon skin barrier disruption and may explain exaggerated inflammatory responses that are observed in disease states characterized by epidermal dysfunction. Pharmacological inhibition of FPR1 or NLRC4 represents a potential therapeutic target. In this study, we identify a novel pathway involving formylpeptide receptor (FPR)1-NOD-like receptor (NLR)C4 inflammasome activation to drive proinflammatory responses in barrier-disrupted skin. We demonstrate that this pathway is active in different types of barrier disruption/dysfunction (mechanical, chemical and genetic) that amplify skin inflammation. We further demonstrate that this occurs through the induction of endoplasmic reticulum (ER) stress involving PERK-eIF2 alpha-CHOP signalling in keratinocytes. We also show that aged skin is more sensitive to barrier disruption by tape stripping with more robust inflammatory responses and FPR1-ER stress-NLRC4 activation. Lastly, we demonstrate the therapeutic utility of inhibiting either FPR1 or NLRC4 signalling and show that this leads to the normalization of skin barrier dysfunction.