Abstract
Psoriasis is a chronic inflammatory skin disease that affects 2–3% of the global population, and there is still no known possibility of a cure. Lipoxin A4 (LXA4), an endogenous lipoxygenase-derived eicosanoid mediator, has potent dual pro-resolving and anti-inflammatory properties. BML-111 (5(S)-6(R)-7-trihydroxyheptanoic acid methyl ester), a lipoxin receptor agonist, has been previously confirmed to be equivalent to LXA4 in the anti-inflammatory processes. High mobility group box 1 (HMGB1) serves as an inflammatory cytokine when secreted extracellularly in psoriatic lesions and is involved in the development of psoriasis. Therefore, we investigated the effects of LXA4 and BML-111 on the HMGB1 signaling cascade and inflammation in lipopolysaccharide (LPS)-induced keratinocytes and imiquimod (IMQ)-induced psoriasiform dermatitis in mice. In the present study, we found that treatment with BML-111 attenuated the development of IMQ-induced psoriasiform dermatitis. Furthermore, treatment with BML-111 and LXA4 inhibited HMGB1 translocation from the nucleus to cytoplasm and downregulated the expression of toll-like receptor 4 (TLR4), receptor for advanced glycation end products (RAGE), p-ERK1/2, nuclear NF-κB p65, and proinflammatory cytokines in vivo and in vitro. Our findings indicate that LXA4 and its analog may be potential therapeutic candidates for psoriasis because of their ability to modulate the translocation and expression of HMGB1.
Highlights
Psoriasis is a chronic inflammatory skin disease that affects 2–3% of the global population[1]
Using co-immunoprecipitation from whole cell lysates of keratinocytes, we found that LPS could induce the acetylation of High mobility group box 1 (HMGB1), but the acetylated HMGB1 was significantly decreased by Lipoxin A4 (LXA4) preincubation
It is known that the etiologies of psoriasis are complex, and the additional mechanisms by which LXA4 confers protection in psoriasis need further investigation
Summary
Psoriasis is a chronic inflammatory skin disease that affects 2–3% of the global population[1]. HMGB1 binds to receptors, including receptor for advanced glycation end products (RAGE) and toll-like receptors (TLRs), such as TLR2 and TLR4 This leads to signal transduction that elicits cellular responses including upregulation of proinflammatory cytokines (e.g., TNF-α, IL-1β, and IL-8) and acute inflammation[9, 10]. A recent study has demonstrated that HMGB1 secreted from keratinocytes can facilitate the expression and secretion of IL-18 by an autocrine mechanism, contributing to the development of psoriasis[14]. Our previous studies have suggested that LXA4 inhibits the growth of normal human epidermal keratinocytes (NHEKs) and their inflammatory cytokine/chemokine production, while its inhibitory effects might be associated with the cyclinD1/P16INK4A, ERK1/2, and NF-κB signal transduction pathways[17, 18]. In in vitro experiments involving NHEKs, LXA4 was applied, while in in vivo experiments involving IMQ-induced psoriasis-like skin in mouse model, BML-111 was used to mimic the effects of LXA4
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