The Significance of IL-36 Hyperactivation and IL-36R Targeting in Psoriasis

Abstract

Psoriasis is an immune-mediated inflammatory skin disease that involves mainly T helper (Th)17, Th1 and Th22 lymphocytes, which cause hyper-proliferation of the epidermis with aberrant differentiation of keratinocytes, and local production of chemokines and cytokines. These fuel a self-amplifying loop where these products act on T cells to perpetuate cutaneous inflammatory processes. Among the various inflammatory mediators involved, interleukin (IL)-36 cytokines are important for the recruitment and activation of neutrophils and Th17 cells in psoriatic skin. In particular, IL-36s induce chemokines and cytokines interfere with differentiation/cornification programs in the epidermis, as well as promote pathological angiogenesis and endothelial cell activation. IL-36 cytokines belong to the IL-1 family, and comprise IL-36α, IL-36β, and IL-36γ agonists as well as IL-36 receptor antagonist and IL-38 antagonists. IL-36 cytokines are up-regulated in psoriatic epidermis, and their expression is strongly induced by TNF-α and IL-17. Contrarily, IL-38 antagonist is downregulated, and its impaired expression may be relevant to the dysregulated inflammatory processes induced by IL-36. Here, we discuss on the pathogenic mechanisms leading to the altered balance of IL-36 agonists/antagonists and the significance of this dysregulation in psoriasis. Collection of the information will provide a theoretical basis for the development of novel therapeutic strategies based on IL-36 agonist/antagonist manipulation in psoriasis.

Keratinocyte interleukin-36 receptor expression orchestrates psoriasiform inflammation in mice

“…Loss of expression of Il36r in keratinocytes results in similar levels of protection from psoriasiform inflammation to those observed in Il36r 2/2 mice In an effort to identify which cell types play an instructive role in mediating IL-36-driven dermal inflammation, we generated a novel Il36r floxed (Il36r fl/fl ) mouse to facilitate cell-specific deletion of Il36r gene, its expression, and responses ( Fig S1). Although IL-36 family cytokines have been reported to stimulate various cell subsets of immune and stromal origin in the skin, we sought to specifically examine the role of keratinocytes given their reported expression of the IL-36 receptor among human patients, responses to IL-36 stimulation ex vivo, and established role in the pathogenesis of psoriatic disease (Blumberg et al, 2007(Blumberg et al, , 2010Carrier et al, 2011;Tortola et al, 2012;Mahil et al, 2016;Madonna et al, 2019). To address this question, we crossed the Il36r fl/fl mouse with K14Cre + transgenic mice, in which the Cre recombinase is expressed in keratinocytes under the control of the keratin-14 gene promoter, to generate mice in which Il36r expression was specifically deleted among keratinocytes in the skin (Il36rΔK mice) (Wang et al, 1997;Dassule et al, 2000).…”

“…It has been previously reported that IL-36 family cytokines can promote their own expression in inflamed skin and possibly act in a feed forward fashion, in tandem with other pathogenic cytokines, to perpetuate inflammation and disease pathogenesis (Milora et al, 2015;Hernandez-Santana et al, 2019;Madonna et al, 2019). Therefore, we investigated whether loss of IL-36r activity among keratinocytes might alter the induction of IL-36 family gene expression in inflamed skin.…”

“…In this regard, it is noteworthy that dendritic cells have been shown to play a critical role in mediating IL-36-dependent psoriasiform inflammation in this model. It is tempting to speculate that these cells, upon activation by mediators other than IL-36, can provide an important source of IL-36 family expression in this setting (Tortola et al, 2012;Numata et al, 2018;Madonna et al, 2019). Together, these findings also have direct relevance to the "feedforward" model of psoriatic inflammation, wherein T-cell-derived IL-17 family cytokines can act in synergy with IL-36 family members, as well as other inflammatory mediators, to promote keratinocyte hyperplasia characteristic of disease (Milora et al, 2015;Campbell et al, 2017;Pfaff et al, 2017).…”

Resolution of plaque-type psoriasis: what is left behind (and reinitiates the disease)

“…This may be in particular important for pustular psoriasis, in which IL-1/IL-36 plays an important role in the pathogenesis [87][88][89]. A vicious loop between AMPs such as cathelicidin (LL-37) and IL-36 signaling may drive psoriatic disease [90][91][92][93]. In fact, IL-36 receptor blockade revealed promising results in pustular psoriasis [94] and may also be a therapeutic option in plaque-type psoriasis [95].…”

Interleukin (IL)-17/IL-36 axis participates to the crosstalk between endothelial cells and keratinocytes during inflammatory skin responses

“…In the psoriasis context, IL-36 cytokines, together with IL-17A, impair keratinocyte differentiation by inducing a proinflammatory skin phenotype [22]. Importantly, IL-36 family impacts on immune response initiation by acting on dendritic and Langerhans cells, recruiting neutrophils, and promoting CD4+ T cell proliferation [23,24]. HDMECs also express IL-36 receptor and respond to IL-36γ stimulation by up-regulating adhesion molecule expression and augmenting chemokine secretion [25].…”