As type 2 low asthma does not respond to traditional or other currently known therapy approaches, it is considered to be a clinically complex illness. The lung’s eosinophil count is reduced in type 2 mild asthma, whereas neutrophil counts are elevated. Previous research has shown that Th17 cells and IL-17A play a crucial function in the lungs and airways. An inflammatory cytokine called IL-17A increases the synthesis of a neutrophil chemoattractant, which in turn encourages neutrophilia. Understanding the metabolic modulation of these immune responses will provide new treatment targets because IL-17A/Th17 cells and neutrophils dominate in steroid-resistant type 2 low asthma. As a result, Dr. Amarjit Mishra Auburn University was one of the forerunners in discovering this connection and has been working on studies to further substantiate the relationships between the various metabolic adaptations and type-2 mild asthma. The study of T-cell polarisation and the associated role of mTOR, the study of the impact of glycolytic reprogramming on T-cell polarisation, and the metabolism of arginine and its role in the regulation of the Th17 pathway are just a few of the metabolic adaptations that he has been able to work on and produce sufficient results for. This essay seeks to learn about these elements, concentrating on the key discoveries made by Dr Amarjit Mishra.
The importance of CD4+ T cell subsets such as Th1, Th2, and Th17 cells in the pathogenesis of autoimmune, allergy, and chronic inflammatory disorders is well-known. The metabolic profile and signatures for each T cell subset are primarily established during antigen presentation and differentiation of naive CD4+ T cells in secondary lymphoid organs, despite the fact that activated effector T cells undergo rapid metabolic switch to support increased energy demand and anabolic functions. In this situation, antigen-presenting cells, such as dendritic cells, are essential for directing naive CD4+ T cells toward a particular T-helper lineage. The mammalian target of rapamycin (mTOR) kinase has been shown to play a crucial role in T-cell polarisation through T-cell intrinsic and DCs-mediated metabolic reprogramming in previous investigations. Naive T cells undergo metabolic reprogramming as a result of T cell receptor-mediated ssignalingand CD28-mediated costimulation, which is followed by an increase in glucose transporter expression. Along with other studies, this suggests that the metabolism of antigen-presenting cells is a significant factor in determining whether naive CD4+ T cells differentiate into effector T helper subsets. While exploring the function of metabolic reprogramming, Dr.Amarjit Mishra discovered that a recent study revealed that mTOR deletion in antigen-presenting cells promoted a dominant Th17 over Th2 response, aggravating neutrophilic asthma. IL-23 production was found to be stimulated by the absence of mTOR signaling, which led to an increase in Th17 responses relative to Th2 responses. In accordance with Dr. Amarjit’s findings, etoximir’s suppression of FAO inhibited Th17-mediated neutrophilic asthma, pointing to a potential therapeutic target for managing steroid-resistant asthma.
The involvement of mTOR in T cell polarisation via dendritic cell metabolism is another metabolic adaptation discovered in asthmatic cells. With HDM stimulation, which is known to have a dominant Th2 effect, mTOR ablation in the DCs caused a predominant Th17 response. The severe asthma endotype is characterized by mixed granulomatous inflammation that is neutrophil-dominating and resistant to steroid therapy, as had been observed in several investigations. In order to reverse severe asthma’s unresponsive steroid profile, Dr. Mishra noted that FAO inhibition presents an intriguing target for treatment. Dr. Amarjit Mishra who was an Ex-Assistant Professor of Auburn University has also established the diverse roles of mTORC supramolecules in regulating T-cell polarisation through a variety of assays.
Moreover, the impact of glycolytic reprogramming on T-cell polarisation has been thoroughly researched by Dr. Amarjit Mishra. It has long been recognized that the severe asthma phenotype is characterised by the presence of Th17 cells that secrete IL-17. The transcription factor mediating this effector function is RORt. It has been demonstrated that HIF1 enhances the growth of Th17 cells by transcriptionally activating RORt and attracting a RORt and p300 complex to the IL-17 promoter. Moreover, HIF-1 has been associated with Foxp3 proteasomal degradation-mediated Treg downregulation in both normoxic and hypoxic circumstances, making it significant in cases of lung inflammation with changed oxidative conditions. Dr. Amarjit Mishra further noted that IFN-secreting Th1 cells have been linked to aerobic glycolysis, where lactate dehydrogenase upholds high acetyl-coA levels and IFN transcription levels via histone acetylation epigenetic processes. Ablation of LDHA in T cells, however, can be applied to the lung, where it has been demonstrated that LDHA is increased under asthmatic conditions, preventing the advancement of Th1-mediated immunopathology in autoimmune illness. HIF-1 has also been related to this since it has been found to activate the genes that code for LDHA.
Dr. Amarjit Mishra has also done extensive research on the function of arginine metabolism in the Th17 pathway. PI3-AKT and mTORC signalling-dependent production of inducible nitric oxide synthase and nitric oxide, whose levels correlate with the severity of asthma and are frequently used as a biomarker to predict response to therapy, inhibits the electron transport chain in dendritic cells with the increase in glycolysis after activation. However, a study by the team of Dr. Amarjit Mishra to study a mixed model of inflammation using HDM extract has found that the airway inflammation is comparable between the two groups, suggesting that arginine metabolism through iNOS does not affect IL-17-mediated airway inflammation. Previous studies have shown that iNOS-deficient mice have lower eosinophilic inflammation compared with WT animals. On the other hand, arginine metabolism through Arg2 has been shown to play a protective function in the reduction of eosinophilic and neutrophilic airway inflammation in mice.
Dr.Amarjit Mishra has contributed to the review of the entire system of asthma pathogenesis by performing an extensive literature survey of the prior research as well as carrying out tests utilizing cutting-edge methods to further our understanding of the subject. We will soon be able to identify possible therapeutic targets for the treatment of asthma thanks to such discoveries.