Persistent Release of IL-1s from Skin Is Associated with Systemic Cardio-Vascular Disease, Emaciation and Systemic Amyloidosis: The Potential of Anti-IL-1 Therapy for Systemic Inflammatory Diseases

Abstract

The skin is an immune organ that contains innate and acquired immune systems and thus is able to respond to exogenous stimuli producing large amount of proinflammatory cytokines including IL-1 and IL-1 family members. The role of the epidermal IL-1 is not limited to initiation of local inflammatory responses, but also to induction of systemic inflammation. However, association of persistent release of IL-1 family members from severe skin inflammatory diseases such as psoriasis, epidermolysis bullosa, atopic dermatitis, blistering diseases and desmoglein-1 deficiency syndrome with diseases in systemic organs have not been so far assessed. Here, we showed the occurrence of severe systemic cardiovascular diseases and metabolic abnormalities including aberrant vascular wall remodeling with aortic stenosis, cardiomegaly, impaired limb and tail circulation, fatty tissue loss and systemic amyloid deposition in multiple organs with liver and kidney dysfunction in mouse models with severe dermatitis caused by persistent release of IL-1s from the skin. These morbid conditions were ameliorated by simultaneous administration of anti-IL-1α and IL-1β antibodies. These findings may explain the morbid association of arteriosclerosis, heart involvement, amyloidosis and cachexia in severe systemic skin diseases and systemic autoinflammatory diseases, and support the value of anti-IL-1 therapy for systemic inflammatory diseases.

Biomarkers for atopic dermatitis

“…In chapter 7 we are the first to show that serum IL-1Rα, IL-1β and IL-1R1 levels are significantly different in AD compared to healthy controls. This supports the concept of an inflammatory skin march, 58,59 in which spilled-over IL-1s from inflamed skin end up into the circulation, thereby affecting distant organs and causing cardiovascular changes. Whether serum levels of IL-1s decrease during treatment, and the subsequent effect on cardiovascular risk factors, is unknown and has yet to be studied.…”

“…57 The association between adult AD and CVD, would be consistent with a recent study that showed the occurrence of severe CVD and metabolic abnormalities in a mouse model of severe dermatitis resulting from persistent release of IL-1 family cytokines from the skin. 58 Interestingly, these pathologies were ameliorated by combination treatment with anti-IL-1α-and anti-IL-1β neutralizing antibodies. In chapter 7 we are the first to show that serum IL-1Rα, IL-1β and IL-1R1 levels are significantly different in AD compared to healthy controls.…”

The association with cardiovascular disease and type 2 diabetes in adults with atopic dermatitis: a systematic review and meta-analysis

“…A very recent study showed an increased occurrence of cardiovascular risk proteins in serum . Finally, one mouse study showed that persistent interleukin (IL)‐1 secretion from the skin was associated with CVD, and in line with this observation, an ‘epidermal IL‐1 march’ was recently described as a potential link between the skin and vascular disease in AD …”

Autoimmunity and Cytokine Imbalance in Inherited Epidermolysis Bullosa

“…IFN-γ is considered a prototypic proinflammatory biomarker of autoimmune inflammation, and its administration to mice results in accelerated autoimmune diseases [23]. In experimental animals, persistent release of IL-1 family members has been associated with the occurrence of severe systemic cardiovascular diseases and metabolic abnormalities, including aberrant vascular wall remodeling with aortic stenosis, cardiomegaly, impaired limb, tail circulation, fatty tissue loss and systemic amyloid deposition in multiple organs with liver and kidney dysfunction [24]. Increases in IL-6 could have a relevant effect because this cytokine promotes Th17 differentiation.…”