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 data indicate that the IL-17 axis is a critical regulator of the progression of NAFL to NASH. Specifically:

1. Obesogenic-diets drive increases in systemic and hepatic IL-17A expression, along with increased recruitment of hepatic GR-1+ cells (presumed neutrophils)
2. 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
3. Antibody-mediated neutralization of IL-17A significantly reduces obesity-associated hepatocellular damage
4. 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
5. Compared to WT controls, IL-17RA-/- mice, exhibit decreased hepatic expression of enzymes associated with induction of reactive oxygen species (ROS). Together, our findings and the data in the literature suggest that activation of the IL-17A/IL-17RA axis is central to the pathogenesis of NASH.

Ongoing studies are focused on defining: the IL-17RA ligand(s) important in NASH pathogenesis; the IL-17RA-expressing cell type(s) critical for driving NASH; and the cellular and molecular mechanisms central to IL-17 axis-mediated pathogenesis in NASH.

Obesity and obesity-associated inflammation are major risk factors for common, serious medical conditions including, metabolic syndrome, type II diabetes, atherosclerosis, non-alcoholic fatty liver disease, Alzheimer’s disease and diverse cancers. Obesity results from an imbalance between energy intake and expenditure. Further, diverse immune cells and mediators play important roles in modulating the response to excess dietary calories/fat, both centrally and peripherally. The inability to effectively target caloric intake or energy expenditure represents a fundamental therapeutic problem in obesity.

Current medical therapies are hampered by appreciable risks and/or meager long-term efficacy. We have uncovered a novel approach to target an immune-metabolic axis as a therapeutic to obesity via regulation of energy expenditure and adipose tissue lipid handling (lipolysis). Overall, the goals of our studies are to:

1. Define the mechanisms underlying immune-regulation of energy expenditure and adipose tissue lipid handling in experimental models
2. Validate and further define the role of these immune-metabolic axes in regulation of obesity and adipose tissue handling in humans.

Specifically, complementary approaches employing genetically modified mice, pharmacological tools and human samples (body composition, metabolic efficiency, mitochondrial function, lipolysis, glucose (dys)metabolism, (dys)lipidemia, WAT inflammation, modulation of transcription factors/networks associated with obesity) are used to define mechanisms of immune axes-mediated regulation of obesity and to provide proof of principal findings in humans. Importantly, as this pathway of immune action is clearly targetable, uncovering the mechanisms underlying immune axes-mediated regulation of obesity holds a significant promise for the development of novel therapeutic approaches.

Obesity is a major risk factor for cardiovascular disease (CVD) and non-alcoholic fatty liver disease (NAFLD). NAFLD, a spectrum of disorders ranging from steatosis to steatohepatitis and cirrhosis promotes CVD development. In turn, CVD is the most common cause of mortality in NAFLD patients. Experimental models of CVD and NAFLD do not fully recapitulate human disease. Recent studies suggest that housing temperature profoundly alters mouse physiology and immune responses—something that may directly impact our ability to better model CVD and NAFLD in mice. While it is well accepted that intestinal microbiome and obesity-associated inflammation—something known to regulate and be regulated by intestinal microbiome—is a central components of NAFLD and CVD pathogenesis, the specific immune pathway(s) and their interplay with intestinal microbiome in orchestrating NAFLD progression are poorly defined and represent a major knowledge gap in the field.

Notably, thermoneutral housing in the context of obesogenic diet stress accelerates development of obesity and exacerbates CVD and NAFLD pathogenesis—something dependent on immune activation and intestinal microbiome colonization. Thus, thermoneutral housing uncovers the relevance of intestinal microbiome-driven activation of immune responses in the pathogenesis of obesity driven sequelae. Ongoing studies aim to determine the mechanisms underlying the thermoneutrality-driven immune modulation, intestinal microbiome colonization and pathogenesis of obesity associated sequlae.

Preterm birth, a leading cause of neonatal morbidity and mortality, affects nearly 500,000 babies annually in the US. Infection and inflammation are thought to be the leading cause of preterm birth. Despite the clinical and public health significance, the molecular trigger(s) and immune pathways underlying the pathogenesis of preterm birth remain under-defined and represent a major gap in knowledge. Further, no specific therapies are available. Thus, there is a clear need for novel preventive and therapeutic approaches to premature birth.

Pregnant women exhibit increased susceptibility to a wide spectrum of infections (e.g, Influenza virus, Listeria species) that are directly linked with pregnancy outcomes. A combined recognition of viral and bacterial molecular patterns, coined a “two-hit hypothesis”, has been proposed as a central regulator of increased susceptibility to preterm birth. Ongoing studies are focused on defining how the viral insults predispose to a secondary bacterial infection and induction of preterm birth. Specifically, we aim to define the critical immune mediators, responding cell type(s), signaling pathways and cellular and molecular mechanisms underlying increased susceptibility to infection/inflammation-driven preterm birth.