Abstract
We recently developed a partial peptide of receptor activator of nuclear factor-кB ligand (RANKL) known as microglial healing peptide 1 (MHP1-AcN), that inhibits Toll-like receptor (TLR)-related inflammation through RANKL/RANK signaling in microglia and macrophages without promoting osteoclast activation. The abnormal activation of TLRs contributes to the initiation and maintenance of psoriasis, which is a chronic inflammatory skin disease that involves the aberrant expression of proinflammatory cytokines and the subsequent dermal γδ T cell and T helper 17 (Th17) cell responses. The inhibition of TLR-mediated inflammation provides an important strategy to treat psoriasis. Here, we examined the preventative effects of MHP1-AcN in a mouse model of imiquimod (a TLR 7/8 agonist)-induced psoriasis. Topical imiquimod application induced psoriasis-like skin lesions on the ear and dorsal skin. Systemic administration of MHP1-AcN by daily subcutaneous injection significantly prevented the development of skin lesions, including erythema, scaling and thickening. Mice treated with MHP1-AcN showed reduced levels of skin Il6 mRNA at 32 h and reduced levels of Il23 and Il17a mRNA at d9. Serum levels of IL-6 and IL-23 were reduced at 32 h, and IL-17A was reduced at d9. These results indicated that MHP1-AcN could decrease imiquimod-induced IL-6, IL-23 and IL-17A production. MHP1-AcN is potentially an alternative treatment for psoriasis.
Highlights
Psoriasis is one of the most common immune-mediated disorders, and crosstalk between components of the innate and adaptive immune systems greatly contributes to its pathogenesis[1]
Because topical application of IMQ triggers Toll-like receptor (TLR)-mediated inflammation that activates dermal γδ T cells to produce IL-17A2, which plays a critical role in the pathogenesis of psoriasis, we examined serum IL-17A levels in mice
We demonstrated that the novel, modified peptide microglia healing peptide-1 (MHP1)-AcN, which was structurally designed from RANKL and modified with N-terminal acetylation and C-terminal amidation to improve its stability and effectiveness, significantly prevented the development of IMQ-induced psoriasis in mice
Summary
Psoriasis is one of the most common immune-mediated disorders, and crosstalk between components of the innate and adaptive immune systems greatly contributes to its pathogenesis[1]. We speculated that RANKL/RANK signaling may improve psoriasis by inhibiting TLR-mediated inflammation and decrease IL-17A production by dermal γδ T cells. Systemic administration of recombinant RANKL induces osteoporosis[15], which is a problem for clinical applications To solve this problem, we developed a novel peptide, microglia healing peptide-1 (MHP1), which is a partial RANKL peptide. We developed a novel peptide, microglia healing peptide-1 (MHP1), which is a partial RANKL peptide This peptide was shown to inhibit TLR2-, 4-, and 7/8-related inflammation through the RANK signaling pathway without inducing osteoclast differentiation[16,17]. We examined the preventative effects of different doses of MHP1-AcN on psoriatic skin lesions and IL-17A production and determined the optimum dose in a mouse model of IMQ-induced psoriasis. We examined the inhibitory effects of MHP1-AcN on IL-6 production in the R837 (TLR7 agonist)-stimulated macrophage cell line
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