Amino acid limitation stress response in inflammation

How brief dietary limitation helps to cope against various biological insults has been a long-standing scientific question. Evolutionarily conserved homeostatic mechanisms have been identified that sense and respond to nutrient/energy limitations and other biological stresses (1,2). These stress adaptation pathways collectively known as integrated stress response (ISR), which plays a protective role by promoting target cell survival and modulating immune responses. Amino acid limitation induces stress, sensed by general control non-depressible kinase (GCN2, aka EIF2AK4), is an integral part of ISR. Recent studies in animal models of autoimmune and inflammatory diseases have shown that amino acid metabolism and GCN2 driven ISR are crucial in regulation of innate and adaptive immune responses (2,3). However, operative association between amino acid limitation, GNC2 and inflammation is not completely understood. By using an animal model of antibody mediated inflammatory kidney injury, we recently showed that GCN2-driven ISR provides an important negative feedback mechanism that antagonizes immune-mediated kidney injury; this occurs by induction of autophagy (4). Correspondingly, comprehensive studies by Ravindran et al. have revealed that GNC2 mediated amino acid limitation stress is an important negative feedback mechanism dampening gut inflammation and mucosal damage by suppressing T-helper cells 17 (T_H17) response and enhancing autophagy (5). These studies suggest that protein/amino acid limitation or drugs that mimic such events might be an attractive target for modulation of inflammatory and other autoimmune disorders.