Browsing Upstate Medical University by Author "Choudhary, Gourav"
Metabolic Control of Autoimmunity Through AutophagyChoudhary, Gourav (2019)Metabolism plays a key role in immune cell activation and differentiation. Immune cell activation depending on their biosynthetic and bioenergetic needs leads to profound metabolic reprograming. Proinflammatory subsets of immune system cells such as effector T cells show dependency on glycolysis, whereas, regulatory T cells rely on oxidative phosphorylation. Under metabolic stress, immune cells utilize autophagy to overcome nutrient scarcity, an alternate method of recycling amino acids and other metabolic precursors. Limitation of nutrients such as amino acids activates mechanistic target of rapamycin (mTOR) in the immune cells. mTOR acts as a metabolic mediator, associated with mitochondria and metabolic needs of the immune cells. Homeostasis between mTOR activation and autophagy decides the fate and functionality of specific immune cells. The activation of mTOR is widely acknowledged in the pathogenesis of SLE, whereas, autophagy has been linked with antigen processing, presentation, and immunoregulation. In this study, we focused on Rab4A, an endosomal GTPase and Transaldolase, a rate limiting enzyme of the pentose phosphate pathway (PPP). Rab4A is over expressed in SLE T cells and facilitates lysosomal degradation of CD4 and CD3. Transaldolase is also overexpressed in T cells from SLE patients and SLE prone mice. First, we examined the role of Rab4A in a pristane-induced mouse model of SLE. Since Rab4A protects from pristane-induced alveolar lung hemorrhage, we tested the hypothesis that Rab4A will also protect from pristane-induced lupus nephritis. We found that overexpression of a constitutively active form of Rab4A limits antinuclear antibody production. Further, we found that Rab4A protects from pristane-induced renal injury by restricting immune complex depositions in the kidney. In additions, we found that Rab4A abrogates kidney-infiltration by lymphocytes and protects from podocyte injury. Furthermore, Rab4A facilitates the lysosomal mediated activation of mTOR. Possibly, the Rab4A mediated activation of mTOR in regulatory T cells leads to suppression of pristane-induced pro-inflammation signaling. In the second part, we investigated if aldose reductase (AR) deficiency can protect from Transaldolase mediated pathogenesis of liver disease. We found a coordinated regulation between AR and TAL, leading to the disease progression.