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. 2018 Oct 30;9(11):1104.
doi: 10.1038/s41419-018-1143-3.

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  1 , Martina Morelli  1   2 , Claudia Scarponi  1 , Elan Z Eisenmesser  3 , Nunzianna Doti  4 , Gianluca Pagnanelli  5 , Emanuela Gubinelli  6 , Cinzia Mazzanti  5 , Andrea Cavani  7 , Menotti Ruvo  4 , Charles A Dinarello  8   9 , Cristina Albanesi  1 , Stefania Madonna  10
Affiliations

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 et al. Cell Death Dis. .

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.

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Conflict of interest statement

The authors declare no conflict of interests.

Figures

Fig. 1
Fig. 1. IL-38 levels are reduced in skin and serum of psoriatic patients and upregulated by secukinumab treatment.
a IHC for IL-38, IL-36Ra, and IL-36γ (all stained in red-brown) was performed on paraffin-embedded sections of biopsies obtained from psoriatic skin (n = 8) including not lesional (NLS) (i), proximal-to-lesion (Pre-LS) (ii), lesional zones of evolving plaques, before (LS T0) (iii) and after 8 weeks (LS T8) (iv) of secukinumab treatment. Sections were counterstained with Mayer’s H&E. One out of eight representative stainings of psoriatic skin biopsies are shown. Bars, 100 μm. Graphs show the mean of four-stage score values for IL-38, IL-36Ra, and IL-36γ ± SD epidermal expression per three different fields of all six sections. *p ≤ 0.05, as assessed by Mann–Whitney U test. b mRNA expression of IL-38, IL-36Ra, and IL-36γ were analyzed by RT-PCR on healthy, NLS, LS T0, and LS T8 biopsies (n = 10) and normalized to HPRT-1 levels. c Cytokine levels were analyzed by ELISA in serum obtained by venous blood of healthy (n = 25) and psoriatic individuals (n = 25) before (Pso T0) and after (Pso T8) secukinumab treatment. b, c The results are shown as individual values and mean. *p ≤ 0.05; p** ≤ 0.01, as assessed by Mann–Whitney U test. d Correlation between the ratio of IL-36γ and IL-38 serum levels and PASI (psoriasis area and severity index) at baseline. e, f Correlations between the ratio of IL-38 or IL-36Ra between T8 and T0 and Δ PASI (Δ PASI, calculated as percentage of PASI reduction) score in psoriatic individuals after secukinumab treatment. Spearman’s test was used for correlation analysis. r indicates the strength of the linear relationship, n indicates the number of values in each plot, and p value shows the probability that the slope of the true relationship is zero. p ≤ 0.05 was considered significant
Fig. 2
Fig. 2. Regulation of the expression and release of IL-38, IL-36Ra, and IL-36γ cytokines by psoriasis-related cytokines in human keratinocytes and endothelial cells.
a, c IL-38, IL-36Ra, and IL-36γ mRNA expression was detected by real-time PCR in keratinocyte cultures undergoing terminal differentiation (4 days post confluency) and HDMEC cultures stimulated with IL-17A (50 ng/ml) and TNF-α (50 ng/ml for keratinocytes and 10 ng/ml for HDMEC), alone or in combination a or in keratinocytes stimulated with IL-22 (50 ng/ml), IFN-γ (200 U/ml, or IL-36γ (50 ng/ml) c, for 6 h. GAPDH mRNA levels were detected for normalization. b, d IL-36 cytokine levels were analyzed by ELISA in supernatants obtained by cell cultures after 24 h cytokine stimulation. All data shown are the mean of three different experiments. *p ≤ 0.01 and **p ≤ 0.001 compared with untreated cultures, as assessed by Mann–Whitney U test
Fig. 3
Fig. 3. IL-38 inhibits IL-36γ-induced P38 and NF-κB signalings, as well as regulates the expression of differentiation markers and inflammatory molecules in human keratinocytes.
All experiments were performed on keratinocyte cultures (n = 3 strains) undergoing terminal differentiation and stimulated or not with IL-36γ in presence or absence of the indicated doses of IL-38 or IL-36Ra. a Protein extracts were obtained from keratinocyte cultures stimulated for 24 h and subjected to WB analysis to detect P38 and P65 phosphorylation. Filters were probed with anti-P38 and -P65 Abs. b Keratinocyte cultures were analyzed for KRT1, KRT10, Loricrin and ΔNp63 expression by WB. a, b β-actin was used as loading control and DI ratio indicates the densitometric intensity of the indicated phosphorylated/unphosphorylated proteins shown in one representative of three different WB. c mRNA levels of CXCL8, CCL20, VEGF-A, IL-6, HBD-2, and LL-37 were detected by real-time PCR analysis in keratinocytes stimulated for 6 h and normalized for GAPDH mRNA levels. TNF-α treatment was used as positive control. d ICAM-1 expression was evaluated by flow cytometry analysis on keratinocytes stimulated for 24 h with IL-36γ (50 ng/ml) and shown as mean fluorescence intensity. All data shown are the mean of three different experiments. c *p ≤ 0.05 and p** ≤ 0.01 compared with untreated or IL-36γ-treated cultures, as assessed by Mann–Whitney U test
Fig. 4
Fig. 4. Ameliorative effects of IL-38 administration on pathological changes of IMQ-induced psoriasiform murine skin lesions.
a Macroscopic views of back skin from mice left untreated (IMQ-) (i), IMQ-treated (IMQ + ) (ii) or co-treated with IMQ and IL-38 (IMQ + /IL-38) (iii) or IMQ and IL-36Ra (IMQ + /IL-36Ra) (iv), both subcutaneously injected, after 5 days. b Representative H&E staining of untreated (i), treated with IMQ cream (ii), in presence of IL-38 (iii) or IL-36Ra (iv). Bars, 500 μm. Subcutaneous injection of IL-38 or IL-36Ra reverted the phenotypic skin changes determined by IMQ. The quantifications of epidermal c, scale thickness d, and immune cell influx e were analyzed as parameters of skin acanthosis and inflammation. Graphs show means of microns of epidermis and stratum corneum thickness, and mean of number of infiltrating immune cells per section (n = 3 sections) ± S.D. per group (n = 8 mice). p* ≤ 0.01 and **p ≤ 0.001 compared with untreated or IMQ-treated groups, as assessed by unpaired Student‘s t test
Fig. 5
Fig. 5. IL-38 reverts the pathological markers in IMQ-induced murine model of psoriasis.
a (i), IMQ-treated (n = 8) (ii) and co-treated with IMQ and IL-38 (IMQ + /IL-38) (n = 8) (iii) or IL-36Ra (IMQ + /IL-36Ra) (n = 8) (iv) shows an upregulated and normalized expression of KRT10 in the epidermis after IL-38 and IL-36Ra treatment, as well as a reduction of VEGF-A expression, and of positive Ki67, Ly6G, CD3, and CD11c cells. Sections were counterstained with Mayer’s H&E and were visually evaluated by a pathologist experienced in dermatology. One out of eight representative stainings is shown. Bars, 500 μm. b Graphs show the mean of number of positive cells or of four-stage score values for KRT10 ± SD per three sections per experimental group (six of eight mice were analyzed). *p ≤ 0.01, **p ≤ 0.001 compared with untreated or IMQ-treated groups, as assessed by unpaired Student‘s t test
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