IL-38 has an anti-inflammatory action in psoriasis and its expression correlates with disease severity and therapeutic response to anti-IL-17A treatment

Laura Mercurio,Gianluca Pagnanelli,Claudia Scarponi,Stefania Madonna,Cristina Albanesi,Cinzia Mazzanti,Menotti Ruvo,Andrea Cavani,Martina Morelli,Emanuela Gubinelli,Nunzianna Doti,Elan Z Eisenmesser,Charles A Dinarello

doi:10.1038/s41419-018-1143-3

Abstract

IL-36 cytokines, a subgroup of IL-1 family, comprise IL-36α, IL-36β, and IL-36γ agonists, abundantly expressed in psoriatic skin, and IL-36RA and IL-38 antagonists. In psoriatic skin, IL-36 cytokines interfere with keratinocyte cornification programs and induce the release of antimicrobial peptides and chemokines active on neutrophils and Th17 lymphocytes. To date, the role of IL-38 antagonist in psoriasis remains to be defined. Here, we demonstrate that skin and circulating IL-38 levels are reduced in psoriatic patients and in other skin diseases characterized by neutrophilic infiltrate. In psoriasis, the balance of IL-36γ agonist/IL-38 antagonist serum levels is in favor of agonists and is closely associated with disease severity. Interestingly, IL-38 is upregulated by anti-IL-17A biological treatment and positively correlates with the therapeutic efficacy of secukinumab in psoriatic patients. The downregulation of IL-38 expression is strictly related to keratinocyte de-differentiation triggered by the inflammatory cytokines IL-36γ, IL-17, and IL-22. Finally, we demonstrate that administration of recombinant full-length IL-38 counteracts in vitro the biological processes induced by IL-36γ in human keratinocytes and endothelial cells and attenuates in vivo the severity of the psoriasiform phenotype induced by IMQ in mice. Such effects are achieved by restoring the physiological programs of keratinocyte proliferation and differentiation, and reducing the immune cell infiltrates.

Highlights

Psoriasis is an immune-mediated skin disease in which interferon (IFN)-γ, tumor necrosis factor (TNF)-α, interleukin (IL)-17, and IL-22 cytokines, released by Th1 and Th17 lymphocytes[1,2], have a pathogenic action by promoting hyperproliferation, interfering with the terminal differentiation and inducing the secretion of pro-IL-36 agonists are strongly expressed in psoriatic skin of individuals affected by plaque psoriasis and generalized pustular psoriasis
Skin levels of IL-38 are reduced in psoriatic patients and in other skin diseases characterized by neutrophilic infiltrate
The interest toward IL-38 in psoriatic context arises from our and earlier observations that its expression is reduced in the epidermis of skin lesions and in the serum of psoriatic patients, as compared with uninvolved or healthy skin, and is inverse to those of IL-36Ra, a well-characterized antagonist of IL-36 cytokines strongly induced in psoriatic lesions[32]

Summary

Introduction

Psoriasis is an immune-mediated skin disease in which interferon (IFN)-γ, tumor necrosis factor (TNF)-α, interleukin (IL)-17, and IL-22 cytokines, released by Th1 and Th17 lymphocytes[1,2], have a pathogenic action by promoting hyperproliferation, interfering with the terminal differentiation and inducing the secretion of pro-. IL-36 agonists are strongly expressed in psoriatic skin of individuals affected by plaque psoriasis and generalized pustular psoriasis. These cytokines have inflammatory effects on many cell targets, mainly keratinocytes, by interfering with their cornification programs and inducing the release of antimicrobial peptides and chemokines active on neutrophils and Th17 lymphocytes[8]. IL-38 has anti-inflammatory effects on mouse models of arthritis and on a model of retinopathy, where it suppresses the secretion of chemokines involved in Th17 pathway and inhibits the pathological processes of vascularization, respectively[21,22]

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