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

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.

SUBMITTER: Mercurio L

PROVIDER: S-EPMC6207563 | biostudies-literature | 2018 Oct

REPOSITORIES: biostudies-literature

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

Mercurio Laura L Morelli Martina M Scarponi Claudia C Eisenmesser Elan Z EZ Doti Nunzianna N Pagnanelli Gianluca G Gubinelli Emanuela E Mazzanti Cinzia C Cavani Andrea A Ruvo Menotti M Dinarello Charles A CA Albanesi Cristina C Madonna Stefania S

Cell death & disease 20181030 11

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 red ...[more]

PMID: 30377293

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Project description:Inflammatory bowel diseases (IBD) and psoriasis are chronic inflammatory conditions belonging to the heterogeneous group of immune-mediated inflammatory diseases (IMIDs). A significant bidirectional link between these two entities has been observed, conditioning an increased risk of IBD in patients with psoriasis and vice-versa. Biological therapies used for IBD may lead to the occurrence of psoriasis as a "paradoxical reaction." The objective of this study is to analyze the current evidence on the association between psoriasis and IBD, particularly finding case reports of the appearance or aggravation of psoriasis under therapy with interleukin-12/23 (IL-12/23) and IL-23 inhibitors. We conducted comprehensive research to identify studies examining the association between psoriasis and IBD and to find case presentations that reported the appearance or aggravation of psoriasis under biologic therapy with IL-12/23 and IL-23 inhibitors up to March 2024. Clinical trials for IL-12/23 and IL-23 inhibitors in IBD were analyzed to find cases of paradoxical psoriasis as registered adverse events. The sources of evidence are PubMed and ClinicalTrials.gov. For each included case report, data on patient characteristics concerning their age, sex, and comorbidities were selected. Moreover, information regarding the indication for biologic therapy, time to onset of paradoxical psoriasis after starting treatment, clinical presentation, and management of the paradoxical psoriasis was extracted. We found 10 reported cases of ustekinumab-induced new-onset or worsening psoriasis and one reported case of paradoxical psoriasis induced by risankizumab in the literature. Four cases of paradoxical psoriasis have been also registered in clinical trials involving ustekinumab treatment in IBD. Psoriasis can constitute a rare paradoxical adverse event of ustekinumab treatment, but further studies are needed to better clarify the cytokine imbalance that leads to this phenomenon induced by inhibition of IL-12/23 and IL-23. Still, few real-world data exist to draw any conclusions, but risankizumab may positively treat psoriasis induced by ustekinumab.

Project description:BackgroundTwo decades after the introduction of oil-based vaccines in the control of bacterial and viral diseases in farmed salmonids, the mechanisms of induced side effects manifested as intra-abdominal granulomas remain unresolved. Side effects have been associated with generation of auto-antibodies and autoimmunity but the underlying profile of inflammatory and immune response has not been characterized. This study was undertaken with the aim to elucidate the inflammatory and immune mechanisms of granuloma formation at gene expression level associated with high and low side effect (granuloma) indices.Groups of Atlantic salmon parr were injected intraperitoneally with oil-adjuvanted vaccines containing either high or low concentrations of Aeromonas salmonicida or Moritella viscosa antigens in order to induce polarized (severe and mild) granulomatous reactions. The established granulomatous reactions were confirmed by gross and histological methods at 3 months post vaccination when responses were known to have matured. The corresponding gene expression patterns in the head kidneys were profiled using salmonid cDNA microarrays followed by validation by real-time quantitative PCR (qPCR). qPCR was also used to examine the expression of additional genes known to be important in the adaptive immune response.ResultsGranulomatous lesions were observed in all vaccinated fish. The presence of severe granulomas was associated with a profile of up-regulation of innate immunity-related genes such as complement factors C1q and C6, mannose binding protein, lysozyme C, C-type lectin receptor, CD209, Cathepsin D, CD63, LECT-2, CC chemokine and metallothionein. In addition, TGF-beta (p = 0.001), IL-17A (p = 0.007) and its receptor (IL-17AR) (p = 0.009) representing TH17 were significantly up-regulated in the group with severe granulomas as were arginase and IgM. None of the genes directly reflective of T(H)1 T cell lineage (IFN-gamma, CD4) or T(H)2 (GATA-3) responses were differentially expressed.ConclusionsGranulomatous reactions following vaccination with oil-based vaccines in Atlantic salmon have the profile of strong expression of genes related to innate immune responses. The expression of TGF-beta, IL-17A and its receptor suggests an involvement of T(H)17 T cell lineage and is in conformity with strong infiltration of neutrophils and macrophages into inflamed areas. Arginase upregulation shows that macrophages in these reactions are alternatively activated, indicating also a T(H)2-profile. To what extent the expression of IL-17A and its receptor reflects an autoimmune vaccine-based reaction remains elusive but would be in conformity with previous observations of autoimmune reactions in salmon when vaccinated with oil-based vaccines.

Dataset Information

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

Publications

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

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