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Nutrient sensor GCN2 plays a crucial role in the maintenance of cellular homeostasis during the condition of amino acid deprivation. Dysfunction in the GCN2 signaling underlies several chronic metabolic diseases. Recent studies highlight the anti-viral potential of GCN2 against RNA viruses such as Sindbis and HIV. However, its effect on dengue virus (DENV) pathogenesis remains poorly understood. Herein, we report that GCN2 deficient cells show increased DENV replication and viral yield in the culture supernatants compared to WT cells infected with DENV. Notably, enhanced DENV replication in GCN2−/− cells is associated with increased COX-2/PGE2 signaling. Conversely, GCN2 overexpression/activation effectively contains DENV infection by inhibiting COX-2/PGE2 signaling. Mechanistically, deletion of GCN2 triggers enhanced production of COX-2/PGE2 through profound activation of Iκκ-NF-κB signaling pathway. Altogether our results unveil a hitherto unrecognized role of GCN2 in DENV pathogenesis, thereby suggesting that targeting the GCN2 pathway might offer a novel therapeutic intervention against DENV infection.

Metabolic adaptation to the changing nutrient levels in the cellular microenvironment plays a decisive role in the maintenance of homeostasis. Eukaryotic cells are equipped with nutrient sensors, which sense the fluctuating nutrients levels and accordingly program the cellular machinery to mount an appropriate response. Nutrients including amino acids play a vital role in maintaining cellular homeostasis. Therefore, over the evolution, different species have developed diverse mechanisms to detect amino acids abundance or scarcity. Immune responses have been known to be closely associated with the cellular metabolism especially amino acid sensing pathway, which influences innate as well as adaptive immune-effector functions. Thus, exploring the cross-talk between amino acid sensing mechanisms and immune responses in disease as well as in normal physiological conditions might open up avenues to explore how this association can be exploited to tailor immunological functions toward the design of better therapeutics for controlling metabolic diseases. In this review, we discuss the advances in the knowledge of various amino acid sensing pathways including general control nonderepressible-2 kinase in the control of inflammation and metabolic diseases.

Ischemia-reperfusion injury is a well-known pathological hallmark associated with diabetic retinopathy, glaucoma and other related retinopathies that ultimately can lead to visual impairment and vision loss. Retinal ischemia pathogenesis involves a cascade of detrimental events that include energy failure, excitotoxic damage, calcium imbalance, oxidative stress and eventually cell death. Retina for a long time has been known to be an immune privileged site; however, recent investigations reveal that retina, as well as the central nervous system (CNS), elicits immunological responses during various stress cues. Stress condition such as reperfusion of blood supply post-ischemia results in the sequestration of various immune cells, inflammatory mediators including cytokines, chemokines etc., to the ischemic region, which in turn facilitates induction of inflammatory conditions in these tissues. The immunological activation during injury or stress per se is beneficial for repair and maintenance of cellular homeostasis but whether the associated inflammation is good or bad, during ischemia-reperfusion injury, hitherto remains to be explored. Keeping all these notions in mind the current review tries to address the immune response and host stress response mechanisms involved in ischemia-reperfusion injury with the focus on the retina.

Ischemia-reperfusion injury is a well-known pathological hallmark associated with diabetic retinopathy, glaucoma, and other related retinopathies that ultimately can lead to visual impairment and vision loss. Retinal ischemia pathogenesis involves a cascade of detrimental events that include energy failure, excitotoxic damage, calcium imbalance, oxidative stress, and eventually cell death. Retina for a long time has been known to be an immune privileged site; however, recent investigations reveal that retina, as well as the central nervous system, elicits immunological responses during various stress cues. Stress condition, such as reperfusion of blood supply post-ischemia results in the sequestration of different immune cells, inflammatory mediators including cytokines, chemokines, etc., to the ischemic region, which in turn facilitates induction of inflammatory conditions in these tissues. The immunological activation during injury or stress per se is beneficial for repair and maintenance of cellular homeostasis, but whether the associated inflammation is good or bad, during ischemia-reperfusion injury, hitherto remains to be explored. Keeping all these notions in mind, the current review tries to address the immune response and host stress response mechanisms involved in ischemia-reperfusion injury with the focus on the retina. [ABSTRACT FROM AUTHOR]