Research

Life Sciences & Biotechnology

Title :	Arsenic-mediated epigenetic regulation of PU,1 and its impact on microglial phagocytosis
Area of research :	Life Sciences & Biotechnology
Principal Investigator :	Dr. Debabrata Ghosh, Csir Indian Institute Of Toxicology Research, Lucknow, Uttar Pradesh
Timeline Start Year :	2024
Timeline End Year :	2027

Details

Executive Summary :

Microglia are the brain macrophages which help in protecting brain from pathogenic infection and also maintain brain homeostasis by secreting various growth factors and clearing tissue debris by phagocytosis. It also helps in neurodevelopment by secreting factors like BDNF, IGF and phagocytosis of synaptic proteins, a process called synaptic pruning. Altered microglial activity is also associated with altered neurobehavior and neuroinflammatory diseases. Microglial phagocytosis is a highly regulated network of specific receptors, regulatory molecule and signaling pathways. PU.1 is a transcription factor generally known for microglial proliferation, but a comprehensive profile of ChIP-Seq-based study enlisted Trem2 as one of its target gene. Therefore, there is a possibility that PU.1 may also be involved in microglial phagocytic process. However, exact molecular mechanism of PU.1 mediated regulation of microglial phagocytosis is yet to be revealed. TREM2 is a phagocytic receptor associated with myelin, amyloid beta and dead cell debri clearance and synaptic pruning. TREM2 plays a vital role in EAE pathogenesis and use of its agonist shown to promote myelin debris clearance in cuprizone-induced demyelinating mouse model. Therefore there is a possibility that PU.1 controls phagocytosis by regulating the expression of Trem2. Our preliminary observations revealed that arsenic exposure increases the microglial phagocytosis in vitro as well as in ex vivo microglia isolated from arsenic and cuprizone-treated animals. Arsenic exposure also increases the expression of PU.1 in microglia. We have also observed that arsenic protects cuprizone-induced demyelination in Balb/c mice. Therefore, based on available literature and our preliminary observation we hypothesized that; Arsenic exposure increases the microglial phagocytosis through TREM2 by controlling PU.1 expression. To test our hypothesis we propose - (1) To study the effect of arsenic on PU.1 expression and its involvement in microglial phagocytosis, (2) To find the underlying mechanism of arsenic-induced altered expression of PU.1, if any, and its impact on phagocytic receptor, and (3) To check the impact of altered microglial phagocytosis in a cuprizone-induced demyelinating mouse model. We will employ in silico analysis, in vitro and in vivo experiments to complete the proposed objectives. Overall, the present study will reveal the underlying mechanism of arsenic-induced epigenetic regulation of microglial phagocytosis by establishing a link between PU.1, phagocytic receptor and microglial phagocytosis (arsenic-PU.1- TREM2?phagocytosis) which can be proven beneficial in demyelination associated anomalies. While exploring the fundamental mechanism of arsenic-induced microglial phagocytosis, it can bring out the translational potential of arsenic which is otherwise known as infamous toxicant.