Enhanced IL-36R signaling promotes barrier impairment and inflammation in skin and intestine

Abstract

Deficiency in interleukin-36R (IL-36R) antagonist caused by loss-of-function mutations in IL-36RN leads to DITRA (deficiency of IL-36 receptor antagonist), a rare inflammatory human disease that belongs to a subgroup of generalized pustular psoriasis (GPP). We report a functional genetic mouse model of DITRA with enhanced IL-36R signaling analogous to that observed in patients with DITRA, which provides new insight into our understanding of the IL-36 family of molecules in regulating barrier integrity across multiple tissues. Humanized DITRA-like mice displayed increased skin inflammation in a preclinical model of psoriasis, and in vivo blockade of IL-36R pathway using anti-human IL-36R antibody ameliorated imiquimod-induced skin pathology as both prophylactic and therapeutic treatments. Deeper characterization of the humanized DITRA-like mice revealed that deregulated IL-36R signaling promoted tissue pathology during intestinal injury and led to impairment in mucosal restoration in the repair phase of chronic dextran sulfate sodium (DSS)–induced colitis. Blockade of IL-36R pathway significantly ameliorated DSS-induced intestinal inflammation and rescued the inability of DITRA-like mice to recover from mucosal damage in vivo. Our results indicate a central role for IL-36 in regulating proinflammatory responses in the skin and epithelial barrier function in the intestine, suggesting a new therapeutic potential for targeting the IL-36R axis in psoriasis and at the later stages of intestinal pathology in inflammatory bowel disease.

Exploring the Role of IL-36 Cytokines as a New Target in Psoriatic Disease

“…In murine models of IL-23 or IL-36α injection, IL-36R antibodies inhibit inflammatory responses, with significant attenuation of skin thickening and expression of psoriasis-relevant genes [ 51 ]. Hovhannisyan and colleagues studied a mouse model with decreased affinity of IL-36Ra to IL-36R, leading to enhanced IL-36R signaling [ 52 ]. Using IL-36R monoclonal antibodies, they demonstrated that IL-36R blockade led to the down-regulation of IL-17A, IL-17F, and IL-23, as well as to reduced skin thickness and reduced IL-6, IL-1β, and TNFα cytokines in the skin [ 52 ].…”

“…Hovhannisyan and colleagues studied a mouse model with decreased affinity of IL-36Ra to IL-36R, leading to enhanced IL-36R signaling [ 52 ]. Using IL-36R monoclonal antibodies, they demonstrated that IL-36R blockade led to the down-regulation of IL-17A, IL-17F, and IL-23, as well as to reduced skin thickness and reduced IL-6, IL-1β, and TNFα cytokines in the skin [ 52 ]. In addition, they found comparable efficacy of anti-IL36R and anti-IL-12p40 (a murine surrogate of ustekinumab) antibodies in reducing IMQ-induced skin inflammation in vivo [ 52 ].…”

“…Using IL-36R monoclonal antibodies, they demonstrated that IL-36R blockade led to the down-regulation of IL-17A, IL-17F, and IL-23, as well as to reduced skin thickness and reduced IL-6, IL-1β, and TNFα cytokines in the skin [ 52 ]. In addition, they found comparable efficacy of anti-IL36R and anti-IL-12p40 (a murine surrogate of ustekinumab) antibodies in reducing IMQ-induced skin inflammation in vivo [ 52 ]. Moreover, while anti-IL36R administration led to decreased levels of IL-36α, IL-36β, and IL-36γ; anti-IL-12p40 antibody only achieved a significant reduction of IL-36γ [ 52 ].…”

“…In addition, they found comparable efficacy of anti-IL36R and anti-IL-12p40 (a murine surrogate of ustekinumab) antibodies in reducing IMQ-induced skin inflammation in vivo [ 52 ]. Moreover, while anti-IL36R administration led to decreased levels of IL-36α, IL-36β, and IL-36γ; anti-IL-12p40 antibody only achieved a significant reduction of IL-36γ [ 52 ].…”

IL-36γ in Enthesitis related Juvenile Idiopathic Arthritis and its association with disease activity.

“…The synovial plasma cells were identified as the primary source of IL-36 expression, which in turn induced production of inflammatory cytokines by fibroblast like synoviocytes (FLS) [11]. In animal models of psoriasis, blockage of IL-36R results in disease amelioration accompanied by reduction in IL-17, leukocyte infiltration and keratinocyte activation [18][19][20]. Most importantly, IL-17 stimulates keratinocytes to produce IL-36 which in turn induce IL-17 production leading to a positive feed-back loop in psoriasis [21], possibly resulting in the dysregulated state of immune response.…”