Abstract
BackgroundDry skin itch is one of the most common skin diseases and elderly people are believed to be particularly prone to it. The inflammasome has been suggested to play an important role in chronic inflammatory disorders including inflammatory skin diseases such as psoriasis. However, little is known about the role of NLRP1 inflammasome in dry skin-induced chronic itch.MethodsDry skin-induced chronic itch model was established by acetone-ether-water (AEW) treatment. Spontaneous scratching behavior was recorded by video monitoring. The expression of nucleotide oligomerization domain (NOD)-like receptor protein 1 (NLRP1) inflammasome complexes, transient receptor potential vanilloid type 1 (TRPV1), and the level of inflammatory cytokines were determined by western blot, quantitative real-time PCR, and enzyme-linked immunosorbent assay (ELISA) kits. Nlrp1a knockdown was performed by an adeno-associated virus (AAV) vector containing Nlrp1a-shRNA-eGFP infusion. H.E. staining was used to evaluate skin lesion.ResultsAEW treatment triggers spontaneous scratching and significantly increases the expression of NLRP1, ASC, and caspase-1 and the levels of IL-1β, IL-18, IL-6, and TNF-α in the spinal cord and the skin of mice. Spinal cord Nlrp1a knockdown prevents AEW-induced NLRP1 inflammasome assembly, TRPV1 channel activation, and spontaneous scratching behavior. Capsazepine, a specific antagonist of TRPV1, can also inhibit AEW-induced inflammatory response and scratching behavior. Furthermore, elderly mice and female mice exhibited more significant AEW-induced scratching behavior than young mice and male mice, respectively. Interestingly, AEW-induced increases in the expression of NLRP1 inflammasome complex and the levels of inflammatory cytokines were more remarkable in elderly mice and female mice than in young mice and male mice, respectively.ConclusionsSpinal cord NLRP1 inflammasome-mediated inflammatory response contributes to dry skin-induced chronic itch by TRPV1 channel, and it is also involved in age and sex differences of chronic itch. Inhibition of NLRP1 inflammasome may offer a new therapy for dry skin itch.
Highlights
Dry skin itch is one of the most common skin diseases and elderly people are believed to be prone to it
To investigate the mechanism that nucleotide-binding oligomerization domainlike receptor pyrin domain-containing 1 (NLRP1) inflammasome is involved in AEW-induced chronic itch, we investigated the effect of NLRP1 inflammasome on TRPV1 activation in dry skin itch model (Fig. 4a)
In this study, we demonstrated that spinal cord NLRP1 inflammasome-mediated inflammatory processes contribute to dry skin-induced chronic itch by activating TRPV1 channel and plays an integral role in itch transduction
Summary
Dry skin itch is one of the most common skin diseases and elderly people are believed to be prone to it. The inflammasome has been suggested to play an important role in chronic inflammatory disorders including inflammatory skin diseases such as psoriasis. Little is known about the role of NLRP1 inflammasome in dry skin-induced chronic itch. Though the sensitization of itch signaling pathways is considered as a potential mechanism for chronic itch [6,7,8], little is known about the pathophysiological process of this disorder. Inflammasomes have been suggested to play an important role in chronic inflammatory conditions including inflammatory skin diseases such as psoriasis [14]. Genome-wide association studies suggest that the NLRP1 haplotype appears in autoimmune diseases associated with psoriasis and vitiligo, and has an effect on skin-specific immune responses [14, 23, 24]. The role of NLRP1 inflammasome in chronic itch remains unclear
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