An analysis of IL-36 signature genes and individuals with IL1RL2 knockout mutations validates IL-36 as a psoriasis therapeutic target

Abstract

Interleukin (IL)-36α, IL-36β, and IL-36γ are innate mediators of acute epithelial inflammation. We sought to demonstrate that these cytokines are also required for the pathogenesis of plaque psoriasis, a common and chronic skin disorder, caused by abnormal T helper 17 (T17) cell activation. To investigate this possibility, we first defined the genes that are induced by IL-36 cytokines in primary human keratinocytes. This enabled us to demonstrate a significant IL-36 signature among the transcripts that are up-regulated in plaque psoriasis and the susceptibility loci associated with the disease in genome-wide studies. Next, we investigated the impact of in vivo and ex vivo IL-36 receptor blockade using a neutralizing antibody or a recombinant antagonist. Both inhibitors had marked anti-inflammatory effects on psoriatic skin, demonstrated by statistically significant reductions in IL-17 expression, keratinocyte activation, and leukocyte infiltration. Finally, we explored the potential safety profile associated with IL-36 blockade by phenotyping 12 individuals carrying knockout mutations of the IL-36 receptor gene. We found that normal immune function was broadly preserved in these individuals, suggesting that IL-36 signaling inhibition would not substantially compromise host defenses. These observations, which integrate the results of transcriptomics and model system analysis, pave the way for early-stage clinical trials of IL-36 antagonists.

Ichthyosis molecular fingerprinting shows profound TH17 skewing and a unique barrier genomic signature

“…53,80,81,97 Our study shows increased mRNA and protein expression of IL-36 family members and IL-36R and highly significant correlations with ichthyosis severity and TEWL, further suggesting IL-36/IL-36R involvement in the T H 17 axis in the ichthyoses, similar to psoriasis. 44,48,49,58,59,96 Our data also extend the prominent severity-associated T H 17 profile in ichthyosis to the blood compartment, supporting an accentuated systemic inflammatory phenotype, particularly in patients with NS.…”

“…In summary, ichthyotic skin and serum have strong T H 17 skewing, with an increase in markers coregulated by IL-17/ TNF-a, preserved epidermal differentiation, and downregulation of lipid metabolism and TJ genes best resembling psoriasis. Our study offers new insights into the possible role of the IL-17 pathway in perpetuating the barrier defects of ichthyosis and advocates for testing of IL-17, IL-36, 96 and IL-23 antagonism in patients with these diseases. Such studies will not only help dissect disease pathogenesis but might also provide hope for better treatment for these devastating disorders.…”

“…Furthermore, the expression of these IL-17/TNF-a-regulated genes significantly correlated with sores on IASI-E, the inflammatory component of ichthyosis severity. Among these psoriasis classifiers are (1) KYNU, which is involved in tryptophan metabolism 91 ; (2) VNN3, expression of which is increased by T H 17/T H 1 but not by T H 2 cytokines, 92,93 as suggested by its increased expression in patients with ichthyosis and psoriasis but not patients with AD; and (3) IL36A/IL36B/ IL36G, proinflammatory cytokines coregulated in keratinocytes by IL-17/TNF-a 94 that amplify IL-17 cytokine production 80,81 and are overexpressed in psoriatic skin, 95,96 discriminating it from AD skin. 53,80,81,97 Our study shows increased mRNA and protein expression of IL-36 family members and IL-36R and highly significant correlations with ichthyosis severity and TEWL, further suggesting IL-36/IL-36R involvement in the T H 17 axis in the ichthyoses, similar to psoriasis.…”

Neutrophil exosomes enhance the skin autoinflammation in generalized pustular psoriasis via activating keratinocytes

“…A recent study showed that another key inflammatory cytokine that drives neutrophil migration in GPP is the IL-36 family of cytokines (12), which mainly functions on keratinocytes and myeloid dendritic cells. For instance, several reports have indicated IL-36g acts as a potent proinflammatory mediator and a valuable biomarker of disease activity in psoriasis pathogenesis (45)(46)(47). The IL-36 cytokine family can increase the expression of chemokines including CXCL1, CXCL8, CCL3, CCL5, and CCL20 in keratinocytes to induce the infiltration of more activated leukocytes (48).…”

Interleukin-36 promotes systemic Type-I IFN responses in severe psoriasis.

“…Numerous studies have shown that IL-36 responses are elevated in PsV skin 2,3,4,5 . Moreover, we have demonstrated that IL-36 stimulates chemokine production and amplifies the effects of IL-17 signalling in psoriatic lesions 3 . Finally, animal studies have established that IL-36 promotes the activation of dendritic cells and the polarization of T lymphocytes into Th17 cells 6 .…”