2. Academic Validation
  3. FPR1 contributes to epidermal barrier dysfunction-induced skin inflammation through NLRC4-dependent keratinocyte activation

FPR1 contributes to epidermal barrier dysfunction-induced skin inflammation through NLRC4-dependent keratinocyte activation

  • Br J Dermatol. 2023 Nov 18:ljad455. doi: 10.1093/bjd/ljad455.
Shuai Shao 1,  Zhongbin Sun 1,  Mengyang Chu 1,  Jiaoling Chen 1,  Tianyu Cao 2,  William R Swindell 3,  Yaxing Bai 1,  Qingyang Li 1,  Jingyi Ma 1,  Zhenlai Zhu 1,  Andrew Schuler 4,  Yolanda Helfrich 4,  Allison C Billi 4,  Zhiguo Li 1,  Junfeng Hao 1,  Chunying Xiao 1,  Erle Dang 1,  Johann E Gudjonsson 4,  Gang Wang 1
Affiliations

Affiliations

  • 1 Department of Dermatology, Xijing hospital, Fourth Military Medical University, Xi'an, Shannxi, 710032, China.
  • 2 Department of Dermatology, Tangdu Hospital, Fourth Military Medical University, Xi'an, Shaanxi 710032, China.
  • 3 Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Texas, USA.
  • 4 Department of Dermatology, University of Michigan, Ann Arbor, Michigan 48109, USA.
PMID: 37979162 DOI: 10.1093/bjd/ljad455
Abstract

Background: Skin barrier dysfunction may both initiate and aggravate skin inflammation. However, the mechanisms involved have remained largely unknown.

Objective: We sought to determine how skin barrier dysfunction enhances skin inflammation and the molecular mechanisms.

Methods: Skin barrier defect mice were established by tape stripping or topical use of acetone on wild type mice, or filaggrin (FLG) deficiency. RNA-sequencing was employed to dissect the differentially expressed genes in skin barrier defect mice. Primary human keratinocytes were transfected with formylpeptide receptor 1 (FPR1) or PERK small interfering RNA (siRNA) to examine the effects of these gene targets. The expressions of inflammasome NLRC4, 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 pro-inflammatory genes, with transcriptomic profiling revealing overexpression of formylpeptide receptor (Fpr1) in the epidermis. Treatment with the FPR1 agonist fMLP in keratinocytes up-regulated the expression of the NLRC4 inflammasome and increased IL-1β secretion through modulation of endoplasmic reticulum stress via the PERK-eIF2α-CHOP pathway. The activation of FPR1-NLRC4 axis was also observed in skin specimens from old healthy individuals with skin barrier defect or elderly mice. Conversely, topical administration with an FPR1 antagonist, or Nlrc4 silencing, led to the normalization of barrier dysfunction and alleviation of inflammatory skin responses in vivo.

Conclusion: 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 seen in disease states characterized by epidermal dysfunction. Pharmacological inhibition of FPR1 or NLRC4 represents a potential therapeutic target.

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