Stromal - Immunology in Metabolic Health and Disease

Another area of laboratory research is to understand the contributions of type 2 immunity - including the role of immune - stromal cell topography - in metabolic health and disease states that span obesity, type 2 diabetes, and metabolic-dysfunction associated steatohepatitis (MASH, formally known as NASH) and downstream liver cirrhosis and HCC. These studies include work in mouse models that focuses on both adipose tissue and the liver.

Obesity promotes local inflammation in visceral adipose tissue that sustains systemic inflammation, insulin resistance, and the development of type 2 diabetes, cardiovascular disease, and others. However, the molecular functions and regulation of normal immune cells in healthy adipose tissue remain poorly understood. We have found that allergic, type 2 immune cells are abundant in healthy, lean adipose tissue and are co-regulated to maintain metabolic health and limit obesity-induced inflammation and insulin resistance. These findings suggest allergic immunity, traditionally associated with pathology (asthma, atopy, allergy) as well as protection from multicellular helminthic worms, also plays a role in the normal physiologic regulation of metabolism, and may participate more broadly in metabolic tissue homeostasis and repair. We seek to better understand the local regulation, interactions, cytokine production, and metabolic impact of the cells in this allergic module, including ILC2s, eosinophils, alternatively activated macrophages (AAM, M2), and Tregs. We anticipate this knowledge will accelerate the development of human therapeutics that can restore balanced anti-inflammatory, allergic-type immune responses that decline in adipose tissue with obesity and old age, limiting the progression of insulin resistance and type 2 diabetes.

Obesity is also associated with the development of liver inflammation, metabolic dysfunction associated steatohepatitis (MASH) and liver cirrhosis/fibrosis. MASH is a progressive form of non-alcoholic fatty liver disease, characterized by fat buildup, inflammation, and hepatocyte injury, and can ultimately lead to liver cirrhosis and increased risk for the development of hepatocellular carcinoma. Type 2 immunity plays a key role in tissue repair and remodeling following injury, but excessive or chronic activation of this allergic module can lead to the development of pathological fibrosis. The precise contributions and regulation of type 2 immune cells in liver fibrosis remain incompletely understood. Our lab is studying the functional role of type 2 resident lymphocytes, type 3/17 lymphocytes that make IL-17A and IL-22, and their coordinated modulation of stromal cells in the pathogenesis of MASH and liver fibrosis. We hope that this research will elucidate the local signals and cellular interactions of tissue-resident lymphocytes and their ‘flavors’ that impact liver physiology, and how these interactions go awry during pathological states.