Obesity is a primary risk factor for the development of non-alcoholic fatty liver disease (NAFLD), a spectrum of disorders ranging from steatosis (NAFL) to steatohepatitis (NASH) to cirrhosis. Despite its clinical and public health significance, the mechanisms underlying the immunopathogenesis of NAFLD remain under-defined. Further, no specific therapies are available. Thus, there is a clear need for novel preventive and therapeutic approaches to NAFLD. The IL-17 family of cytokines plays an essential role in barrier immunity, inflammatory pathology in various autoimmune diseases, and in the pathogenesis of diverse hepatic diseases. The ability of IL-17 signaling to induce the production of cytokines and neutrophil chemokines is central to the biological effects of IL-17 axis. Our novel Preliminary Data indicate that the IL-17 axis is a critical regulator of the progression of NAFL to NASH. Specifically: (a) obesogenic-diets drive increases in systemic and hepatic IL-17A expression, along with increased recruitment of hepatic GR-1+ cells (presumed neutrophils);(b) compared to wild-type (WT) controls, mice with a genetic deletion in the IL-17 receptor complex member IL-17RA exhibit decreased steatohepatitis and hepatocellular damage despite increased steatosis and weight gain after obesogenic diet challenge;(c) antibody-mediated neutralization of IL-17A significantly reduces obesity-associated hepatocellular damage;(d) colonization of mice with segmented filamentous bacteria (SFB), a pathobiont that robustly upregulates IL-17 production by intestinal T cells, exacerbates hepatocellular damage in obese mice- whereas vancomycin- mediated depletion of SFB significantly reduces hepatocellular damage in such mice;and (e) compared to WT controls, IL-17RA-/- mice, exhibit decreased hepatic expression of enzymes associated with induction of reactive oxygen species (ROS). Taken together, our strong preliminary findings and the data in the literature suggest the organizing hypothesis that activation of the IL-17A/IL-17RA axis is central to the pathogenesis of NASH. Studies in this proposal will: (1) determine the IL-17RA ligand(s) important in NASH pathogenesis;(2) define the IL-17RA-expressing cell type(s) critical for driving NASH;and (3) define the cellular and molecular mechanisms central to IL-17 axis-mediated pathogenesis in NASH. The goal of this application is to gain a clear mechanistic understanding of the role of IL-17 axis in the pathogenesis of NASH. The long-term goal of this program is to identify novel preventive and therapeutic strategies for NALFD.

Public Health Relevance

Obesity is a primary risk factor for the development of diverse chronic diseases, including type II diabetes, cardiovascular disease, and non-alcoholic fatty liver disease (NAFLD)-the subject of the current grant. How obesity leads to NAFLD remains poorly understood. We have found that a family of immune molecules is critical for driving the progression of obesity-associated NAFLD in mice. The studies proposed here aim to build on these preliminary insights in order to get a better understanding of the mechanisms by which obesity- associated dysregulation of immune responses leads to NAFLD. The long-term goal of this research program is to devise novel preventive and therapeutic strategies for fatty liver disease.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
3R01DK099222-02S1
Application #
8895814
Study Section
Hepatobiliary Pathophysiology Study Section (HBPP)
Program Officer
Doo, Edward
Project Start
2013-09-05
Project End
2018-07-31
Budget Start
2014-08-01
Budget End
2015-07-31
Support Year
2
Fiscal Year
2014
Total Cost
$87,360
Indirect Cost
$31,360
Name
Cincinnati Children's Hospital Medical Center
Department
Type
DUNS #
071284913
City
Cincinnati
State
OH
Country
United States
Zip Code
45229
Stemmer, K; Kotzbeck, P; Zani, F et al. (2015) Thermoneutral housing is a critical factor for immune function and diet-induced obesity in C57BL/6 nude mice. Int J Obes (Lond) 39:791-7
Harley, Isaac T W; Stankiewicz, Traci E; Giles, Daniel A et al. (2014) IL-17 signaling accelerates the progression of nonalcoholic fatty liver disease in mice. Hepatology 59:1830-9