Life Sciences & Biotechnology
Title : | Targeting neutrophils to improve anti-microbial host defense and enhance resolution of inflammation: Implications in maintaining immune homeostasis in Type 2 Diabetes |
Area of research : | Life Sciences & Biotechnology |
Principal Investigator : | Dr. Manjunath B Joshi, Manipal Academy Of Higher Education, Karnataka |
Timeline Start Year : | 2023 |
Timeline End Year : | 2026 |
Contact info : | manjunath.joshi@manipal.edu |
Details
Executive Summary : | Neutrophils play a crucial role in combating pathogens through mechanisms such as degranulation, phagocytosis, and production of extracellular traps (NETs), which facilitate the clearance of post-infection debris. However, the inability to resolve neutrophils and their components leads to tissue damage, as neutrophils carry powerful proteases and pro-inflammatory cytokines that drive inflammation. Neutrophil-mediated sterile inflammation is a central mechanism in the pathogenesis of diseases like Type 2 Diabetes (T2D). Studies have shown that hyperglycemia induces metabolic reprogramming in neutrophils, leading to insufficient pools of NADPH and impeded response to infections. T2D individuals show increased NETs components in serum, which positively correlate to fasting and post-prandial glucose levels. Elevated IL-6 and homocysteine in T2D induce constitutive NETosis, further activating platelets. Studies have also shown that hyperglycemia reduces the expression of Bax, a pro-apoptotic protein, and delays neutrophil apoptosis, leading to the accumulation of aged neutrophils in inflamed sites. T2D conditions also express increased B2 and Annexin A1 proteins and reduce neutrophil clearance by macrophages. The project aims to establish protocols for neutrophil transfusion using high fat diet and db/db diabetic mouse models. The study will examine response to infections, improvement in survival, and inflammatory mediators related to the neutrophil life cycle. The findings have translational potential for clinical management of T2D-associated infections and timely resolution of inflammation. |
Total Budget (INR): | 43,64,800 |
Organizations involved