Biomaterial Database

Formylpeptide receptor 1 contributes to epidermal barrier dysfunction-induced skin inflammation through NOD-like receptor C4-dependent keratinocyte activation. 2024

Shuai Shao, and Zhongbin Sun, and Mengyang Chu, and Jiaoling Chen, and Tianyu Cao, and William R Swindell, and Yaxing Bai, and Qingyang Li, and Jingyi Ma, and Zhenlai Zhu, and Andrew Schuler, and Yolanda Helfrich, and Allison C Billi, and Zhiguo Li, and Junfeng Hao, and Chunying Xiao, and Erle Dang, and Johann E Gudjonsson, and Gang Wang

Department of Dermatology, Xijing Hospital.

BACKGROUND Skin barrier dysfunction may both initiate and aggravate skin inflammation. However, the mechanisms involved in the inflammation process remain largely unknown. OBJECTIVE 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-1β secretion through modulation of ER stress via the PERK-eIF2α-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.

UI	MeSH Term	Description	Entries
D007249	Inflammation	A pathological process characterized by injury or destruction of tissues caused by a variety of cytologic and chemical reactions. It is usually manifested by typical signs of pain, heat, redness, swelling, and loss of function.	Innate Inflammatory Response,Inflammations,Inflammatory Response, Innate,Innate Inflammatory Responses
D003872	Dermatitis	Any inflammation of the skin.	Dermatitides
D004817	Epidermis	The external, nonvascular layer of the skin. It is made up, from within outward, of five layers of EPITHELIUM: (1) basal layer (stratum basale epidermidis); (2) spinous layer (stratum spinosum epidermidis); (3) granular layer (stratum granulosum epidermidis); (4) clear layer (stratum lucidum epidermidis); and (5) horny layer (stratum corneum epidermidis).
D006801	Humans	Members of the species Homo sapiens.	Homo sapiens,Man (Taxonomy),Human,Man, Modern,Modern Man
D000070576	NLR Proteins	Intracellular signaling proteins that are defined by the presence of a NUCLEOTIDE-binding region and LEUCINE-rich repeats. Their general structure consists of any of a variety of effector domains at their N-termini such as a caspase recruitment domain (CARD), a central nucleotide-binding domain, and a variable number of C-terminal leucine-rich repeats. They are important for pathogen recognition in the INNATE IMMUNE RESPONSE of animals and plants. Members of the NLR protein family include the NOD SIGNALING ADAPTOR PROTEINS.	NOD-like Receptor,Nucleotide-Binding Domain Leucine-Rich Repeat Protein,NLR Protein,NOD-like Receptors,Nucleotide-binding Domain Leucine-rich Repeat Proteins,NOD like Receptor,NOD like Receptors,Nucleotide Binding Domain Leucine Rich Repeat Protein,Nucleotide binding Domain Leucine rich Repeat Proteins,Protein, NLR,Proteins, NLR,Receptor, NOD-like,Receptors, NOD-like
D000091344	Filaggrin Proteins	S100 proteins that aggregate KERATINS. Filaggrin precursor proteins are localized in keratohyalin granules and processed into individual functional filaggrin molecules during terminal epidermis differentiation. Mutations in fillagrins are associated with ICHTHYOSIS VULGARIS.	Filaggrin,Filaggrin Protein,Profilaggrin,Stratum Corneum Basic Protein,Stratum Corneum Basic Protein Precursor,Protein, Filaggrin,Proteins, Filaggrin
D000096	Acetone	A colorless liquid used as a solvent and an antiseptic. It is one of the ketone bodies produced during ketoacidosis.
D000818	Animals	Unicellular or multicellular, heterotrophic organisms, that have sensation and the power of voluntary movement. Under the older five kingdom paradigm, Animalia was one of the kingdoms. Under the modern three domain model, Animalia represents one of the many groups in the domain EUKARYOTA.	Animal,Metazoa,Animalia
D015603	Keratinocytes	Epidermal cells which synthesize keratin and undergo characteristic changes as they move upward from the basal layers of the epidermis to the cornified (horny) layer of the skin. Successive stages of differentiation of the keratinocytes forming the epidermal layers are basal cell, spinous or prickle cell, and the granular cell.	Keratinocyte
D051379	Mice	The common name for the genus Mus.	Mice, House,Mus,Mus musculus,Mice, Laboratory,Mouse,Mouse, House,Mouse, Laboratory,Mouse, Swiss,Mus domesticus,Mus musculus domesticus,Swiss Mice,House Mice,House Mouse,Laboratory Mice,Laboratory Mouse,Mice, Swiss,Swiss Mouse,domesticus, Mus musculus