Retrospective epidemiological studies have demonstrated that patients with chronic inflammatory skin disease have an increased risk for developing and dying of cardiovascular disease (CVD), including myocardial infarction and stroke. Inflammatory cascades that mediate skin disease and CVD have striking similarities including activation of antigen presenting cells and macrophages, involvement of Th1, Th17 and regulatory T cells, and critical roles for IL-12p40, IL-17 and TNF. Whether remote inflammation has the capacity to initiate atherosclerosis and/or thrombosis pathogenesis is as yet undetermined. To determine if remote inflammation can instigate co-morbid complications such as CVD, we engineered a tetracycline-repressible binary mouse model of chronic inflammation by ectopically expressing the angiopoeitin receptor, Tie2 exclusively to keratinocytes (KC). The KC-Tie2 mouse develops unremitting skin inflammation characterized by dermal infiltrating leukocytes and increased proinflammatory cytokines. Most significant for the current proposal is ~33% of KC-Tie2 mice on a wild type background spontaneously develop atherosclerotic plaque and have elevated levels of pro-atherogenic CD11b+Ly-6Chi monocytes. Moreover, the time to occlusive thrombus formation in KC-Tie2 animals is significantly shortened compared to control littermates. The opportunity to study a model of chronic skin-confined inflammation that develops CVD co-morbidities in the absence of any of the standard CVD risk factors (e.g. hyperlipidemia, hypertension, diabetes) provides an innovative preclinical opportunity to identify pro-atherogenic and pro-thrombotic cellular mechanism(s) mediated by long term non-vascular inflammation. We hypothesize that chronic inflammation increases circulating CD11b+Ly-6Chi monocytes and promotes atherothrombosis. Using a combination of mouse molecular genetics, therapeutic targeting strategies utilizing small molecule inhibitors and function blocking antibodies, coupled with bone marrow and skin transplant approaches we propose to identify pro-atherogenic and pro-thrombotic cellular mechanism(s) elicited by chronic skin-specific inflammation. Collectively, our studies will elucidate the cellular basis underlying chronic remot inflammation-mediated atherothrombosis. The results of these studies will provide insight into the etiology and development of novel therapies directed towards CVD co-morbidities associated with chronic inflammatory diseases including rheumatoid arthritis, colitis, gum disease, psoriasis and lupus.

Public Health Relevance

There is an increased prevalence of ischemic heart disease, cerebrovascular disease, peripheral artery disease and an increased risk of death in individuals suffering from chronic inflammatory diseases, such as rheumatoid arthritis (RA), colitis, gum disease, psoriasis and lupus. Understanding the cellular and molecular mechanisms linking remote inflammation and cardiovascular disease will provide new knowledge as to why this relationship exists and more importantly will provide novel therapeutic development strategies directed at the treatment of the cardiovascular co-morbidities associated with chronic inflammation.

Agency
National Institute of Health (NIH)
Institute
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Type
Research Project (R01)
Project #
5R01AR063437-02
Application #
8518172
Study Section
Atherosclerosis and Inflammation of the Cardiovascular System Study Section (AICS)
Program Officer
Cibotti, Ricardo
Project Start
2012-08-01
Project End
2017-07-31
Budget Start
2013-08-01
Budget End
2014-07-31
Support Year
2
Fiscal Year
2013
Total Cost
$335,588
Indirect Cost
$121,838
Name
Case Western Reserve University
Department
Dermatology
Type
Schools of Medicine
DUNS #
077758407
City
Cleveland
State
OH
Country
United States
Zip Code
44106
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Fritz, Yi; Klenotic, Philip A; Swindell, William R et al. (2016) Induction of Alternative Proinflammatory Cytokines Accounts for Sustained Psoriasiform Skin Inflammation in IL-17C+IL-6KO Mice. J Invest Dermatol :
Monin, Leticia; Gudjonsson, Johann E; Childs, Erin E et al. (2016) MCPIP1/Regnase-1 Restricts IL-17A- and IL-17C-Dependent Skin Inflammation. J Immunol :
Wang, Yunmei; Golden, Jackelyn B; Fritz, Yi et al. (2016) Interleukin 6 regulates psoriasiform inflammation-associated thrombosis. JCI Insight 1:e89384
Zhang, Ling-Juan; Sen, George L; Ward, Nicole L et al. (2016) Antimicrobial Peptide LL37 and MAVS Signaling Drive Interferon-β Production by Epidermal Keratinocytes during Skin Injury. Immunity 45:119-30
Li, Yong; Stoll, Stefan W; Sekhon, Sahil et al. (2016) Transgenic expression of human amphiregulin in mouse skin: inflammatory epidermal hyperplasia and enlarged sebaceous glands. Exp Dermatol 25:187-93
Hawkes, Jason E; Gudjonsson, Johann E; Ward, Nicole L (2016) The Snowballing Literature on Imiquimod-Induced Skin Inflammation in Mice: A Critical Appraisal. J Invest Dermatol :
Swindell, William R; Xing, Xianying; Fritz, Yi et al. (2016) Deficiency of myeloid-related proteins 8 and 14 (Mrp8/Mrp14) does not block inflammaging but prevents steatosis. Oncotarget 7:35535-35551
Ward, Nicole L; Bhagathavula, Narasimharao; Johnston, Andrew et al. (2015) Erlotinib-induced skin inflammation is IL-1 mediated in KC-Tie2 mice and human skin organ culture. J Invest Dermatol 135:910-3
Ward, Nicole L (2015) Introduction to a special issue on Skin disease, immune response and cytokines. Cytokine 73:309-10

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