UNDERSTANDING OF IMMUNE AND HSC REGULATION IN METABOLIC AND INFLAMMATORY DISORDERS

Immune cells are critical for homeostasis, but can also lead to inflammation and tissue damage. Neutrophils being the most abundant leukocytes are critical in the fight against pathogens including bacteria, fungi, and viruses. Besides their prominent role in acute inflammatory disorders, several new findings are now started to investigate the role of neutrophils in normal tissue and chronic conditions. Indeed, the concept of meta-inflammation i.e. low-grade inflammation has been suggested to play a central role in metabolic disorders like diabetes and obesity. Here, we are focusing on the role of neutrophils and its putative subtypes in insulin resistance and type 2 diabetes metabolic diseases.

Our research interests are to understand the dysregulated signaling pathways that cause altered immune cell recruitment and function during infection/inflammatory or disease conditions. As immune cells are generated by hematopoietic stem cells (HSCs), our laboratory interest is further extended to HSC biology and studying HSC regulation and bone marrow niche, we aim to identify approaches for expansion of HSCs in-vitro, a key process for clinical use. Our long-term goal is to identify new targets and small molecules to regulate immune cells functions and HSC function for therapeutic purposes in the future. As part of the drug discovery program at CDRI, we are targeting diverse immune cells functions for screening drug-like small molecules and natural products.

High infiltration of neutrophils is observed in the liver and other metabolic tissues under diabetic conditions. In addition, there is a substantial increase in granulopoiesis in diabetic mice. Importantly neutrophil count increases but neutrophil functions like phagocytosis, ROS, and chemotaxis dampen significantly during insulin resistant and diabetic conditions. our data so far suggest an important role of neutrophil infiltration in tissue damage and metabolic insults. Redox enzymes- NADPH Oxidase and iNOS deficient mice exhibited insulin resistance and neutrophils in these mice exhibit defective anti-microbial functions. Further investigations are unraveling the role of these neutrophils in the development of insulin resistance and type 2 diabetes. The classical view of neutrophils as a homogenous population has also been challenged recently with the identification of neutrophil heterogeneity. Results from our lab suggest drastic neutrophil plasticity in different metabolic organs. We are further investigating therapeutic targets through molecular mechanism approaches to target neutrophil plasticity.

The overall goal is to identify dysregulated immune functions and pathways that may be further utilized for therapeutic purposes in the future.