Interleukin-1β Interferes with Epidermal Homeostasis through Induction of Insulin Resistance: Implications for Psoriasis Pathogenesis

Abstract

Response pathways of the metabolic and the immune system have been evolutionary conserved, resulting in a high degree of integrated regulation. Insulin is a central player in the metabolic system and potentially also in the homeostasis of the skin. Psoriasis is a frequent and often severe autoimmune skin disease, clinically characterized by altered epidermal homeostasis, of which the molecular pathomechanisms are only little understood. In this study, we have examined a potential role for insulin signaling in the pathogenesis of this disease. We show that IL-1β is present in high quantities in tissue fluid collected via microdialysis from patients with psoriasis; these levels are reduced under successful anti-psoriatic therapy. Our results suggest that IL-1β contributes to the disease by dual effects. First, it induces insulin resistance through p38MAPK (mitogen-activated protein kinase), which blocks insulin-dependent differentiation of keratinocytes, and at the same time IL-1β drives proliferation of keratinocytes, both being hallmarks of psoriasis. Taken together, our findings point toward insulin resistance as a contributing mechanism to the development of psoriasis; this not only drives cardiovascular comorbidities, but also its cutaneous phenotype. Key cytokines inducing insulin resistance in keratinocytes and kinases mediating their effects may represent attractive targets for novel anti-psoriatic therapies.

Interplay between CXCR2 and BLT1 Facilitates Neutrophil Infiltration and Resultant Keratinocyte Activation in a Murine Model of Imiquimod-Induced Psoriasis

“…7A). Our findings reinforce the similarity of IMQ model to human disease in which IL-1b and CXCR2 ligands are upregulated (17,29). Furthermore, IL-19 family cytokines were upregulated, as well as human psoriatic lesion (26) and IL-23-induced murine psoriasis-like dermatitis (26).…”

“…These findings raise the possibility that neutrophils might be the main source of secreted IL-1b. Because IL-1b is implicated in the pathogenesis of psoriasis (17), neutrophils likely play important roles in psoriatic skin inflammation as the primary cellular source of IL-1b.…”

Interleukin-1β-induced Reduction of CD44 Ser-325 Phosphorylation in Human Epidermal Keratinocytes Promotes CD44 Homomeric Complexes, Binding to Ezrin, and Extended, Monocyte-adhesive Hyaluronan Coats

“…In inflammatory skin diseases like psoriasis, IL-1␤ is increased and is supposed to attract inflammatory cells. Hyaluronan accumulates below the basal cells in psoriatic skin (102) and could bind macrophages found in psoriatic epidermal microabscesses (103,104), together with neutrophils and T cells (103,104), which could all use the IL-1␤-induced extended hyaluronan coats around keratinocytes to facilitate their invasion in the epidermis. In addition, in an in vivo inflammation, hyaluronan synthesis is probably turned on in keratinocytes by concurrent factors like KGF, induced in dermal cells by IL-1␤.…”

Bioinformatic analysis of the effect of type II diabetes on skin wound healing

“…Diabetes is ranked as the third-most common chronic disease threating human health after cancer and cardiovascular disease (Sakai and Tagami, 2010;Buerger et al, 2012). Diabetic skin is vulnerable to damage; once injured, it is often recurrent, even causing intractable refractory ulcers (Spravchikov et al, 2001).…”