IL-22/STAT3-Induced Increases in SLURP1 Expression within Psoriatic Lesions Exerts Antimicrobial Effects against Staphylococcus aureus

Abstract

Background SLURP1 is the causal gene for Mal de Meleda (MDM), an autosomal recessive skin disorder characterized by diffuse palmoplantar keratoderma and transgressive keratosis. Moreover, although SLURP1 likely serves as an important proliferation/differentiation factor in keratinocytes, the possible relation between SLURP1 and other skin diseases, such as psoriasis and atopic dermatitis, has not been studied, and the pathophysiological control of SLURP1 expression in keratinocytes is largely unknown.ObjectivesOur aim was to examine the involvement of SLURP1 in the pathophysiology of psoriasis using an imiquimod (IMQ)-induced psoriasis model mice and normal human epidermal keratinocytes (NHEKs).ResultsSLURP1 expression was up-regulated in the skin of IMQ-induced psoriasis model mice. In NHEKs stimulated with the inflammatory cytokines IL-17, IL-22 and TNF-α, which are reportedly expressed in psoriatic lesions, SLURP1 mRNA expression was significantly up-regulated by IL-22 but not the other two cytokines. The stimulatory effect of IL-22 was completely suppressed in NHEKs treated with a STAT3 inhibitor or transfected with siRNA targeting STAT3. Because IL-22 induces production of antimicrobial proteins in epithelial cells, the antibacterial activity of SLURP1 was assessed against Staphylococcus aureus (S. aureus), which is known to be associated with disease severity in psoriasis. SLURP1 significantly suppressed the growth of S. aureus.ConclusionsThese results indicate SLURP1 participates in pathophysiology of psoriasis by regulating keratinocyte proliferation and differentiation, and by suppressing the growth of S. aureus.

IL-22 derived from γδ T cells restricts Staphylococcus aureus infection of mechanically injured skin

“…The expression of Defb3 mRNA is strikingly diminished in patients with recurrent S. aureus infections 26 suggesting its importance in controlling the severity of S. aureus infections. The secreted lymphocyte antigen-6/urokinase-type plasminogen activator receptor related protein-1 (SLURP1) encoded by Slurp1 , has been shown to induce proliferation of keratinocytes and suppression of growth of S. aureus 27 . Hence, our finding that the induction of Slurp1 and Defb14 in tape stripped skin is regulated by IL-22 demonstrates that IL-22 possesses a pleiotropic role in the control of S. aureus infection in mechanically injured skin of mice.…”

“…We observed a decrease in the expression of Slurp1 and Defb14 . Both of these proteins have been shown to suppress the growth of S. aureus 26, 27 . These findings suggest that IL-22 acts pleiotropically to inhibit S. aureus infections.…”

Cholinergic signalling mechanisms and early implant healing phases in healthy versus generalized aggressive periodontitis patients: A prospective, case–control study

“…SLURP‐1 can act as allosteric antagonist of the α7nAChR but has also been demonstrated to activate metabotropic‐signalling pathways (Lyukmanova et al, ). SLURP‐1 is secreted at mucosal sites and has also been shown to have both immunomodulatory (Moriwaki et al, ) and antimicrobial properties (Moriwaki et al, ). In addition, SLURP‐1 has been found to inhibit proliferation of oral keratinocytes (Lyukmanova et al, ).…”

“…SLURP-1 is secreted at mucosal sites and has also been shown to have both immunomodulatory (Moriwaki et al, 2007) and antimicrobial properties (Moriwaki et al, 2015). In addition, SLURP-1 has been found to inhibit proliferation of oral keratinocytes (Lyukmanova et al, 2016).…”

Lesional upregulation of SLURP1 immunostaining parallels disease severity in psoriasis vulgaris patients

“…A severe form of palmoplantar keratoderma has been observed in SLURP1‐deficient mice , and SLURP1 mutations were found to be the underlying defect in mal de Meleda in humans . Recently, it was shown that expression of SLURP1 was upregulated in a mouse model of psoriasis induced by imiquimod, suggesting that SLURP1 may also play a role in human psoriasis . This protein features the three‐finger folded structure which has been detected in a family of neurotoxins derived from snakes and frogs.…”