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HomeBUSINESSA Study by Amarjit Mishra - Metabolic Adaptations in Th2-High Asthma

A Study by Amarjit Mishra – Metabolic Adaptations in Th2-High Asthma

Around 400 million individuals worldwide today suffer from asthma, a chronic inflammatory respiratory disease, and this figure is steadily rising. At least two different forms of clinical heterogeneity are present in asthma patients, including Th2-high eosinophilic asthma and Th2-low non-eosinophilic asthma.

In spite of the fact that a number of immunological pathways are progressively being recognised to explain the development and course of the disease, metabolic changes in immune cells have provided new information regarding the pathogenesis of asthma. The assessment and research studies carried out at Auburn University of Alabama in the United States of America are leading the way in the progress of this understanding.

In this article, we present an excerpt of a review by Dr. Amarjit Mishra of Auburn University who has been working to improve understanding of the metabolic adaptation and activation of lung immune cells in the development and regulation of airway inflammation, with a focus on immunometabolic pathways in causing asthma heterogeneity.

Dr. Amarjit Mishra and his team are striving to create promising new therapy strategies by increasing their understanding of how immunometabolic pathways regulate airway inflammation and the aetiology of asthma. The metabolic adjustments associated with the Th2 high form of asthma have been highlighted in this article.

Serum IgE levels, fractional exhaled nitric oxide, blood and sputum eosinophil levels, and type 2 cytokines IL4, IL5, and IL13 are all raised with th2-high asthma. Although innate type 2 lymphoid cells and natural killer cells regulate the innate type 2 inflammatory response in the airways, Th2 immune cells in the lungs aid in the promotion of adaptive immunity.

Yet, the IL-5, IL-13, and IL-4 cytokine production that results from the Th2-mediated lung adaptive immune response is accompanied by a phenotype of eosinophilic inflammation. Pyruvate Kinase M2 expression is one of the significant metabolic modifications emphasised by Amarjit Mishra.

The allergic stimulus-induced Th2 inflammation is initiated by antigen-presenting dendritic cells, which depend on immature mitochondrial oxidative phosphorylation and are regulated by AMPK signalling. Dendritic cells undergo metabolic reprogramming along with a rise in glycolysis for ATP synthesis in the context of early Toll-like receptor activation.

Furthermore, according to Amarjit Mishra of Auburn University, inhibiting STAT3 phosphorylation and IL-1-mediated TSLP release by activating PKM2 via the small molecule activator TEPP46 significantly reduced the eosinophilic inflammation of the airways, subepithelial collagen deposition, as well as mucosal metaplasia brought on by house dust mites.

Amarjit Mishra also discusses the role of the mitochondrial Irg1/itaconate axis in controlling Th2 inflammation as a significant metabolic adaptation. Prior research has established a redox-dependent and related relationship between cross-presentation and allergen absorption by antigen-presenting dendritic cells.

In this respect, Amarjit Mishra and his group have shown that the TCA cycle intermediate itaconate, a mitochondrial metabolite, changes the effector function of dendritic cells, changing the onset of allergic asthma in mice. Itaconate,

which is produced by decarboxylating the TCA cycle intermediate cis-aconitate, is encoded by the immune response gene. By stimulating the allergen in the absence of Irg1, mitochondrial stress and ROS production are increased, which affects metabolic genes and kinetic oxygen consumption rate, impairing mitochondrial redox and the dendritic cells capacity to prime and present the immune system.

Amarjit Mishra and his team’s results suggest that the dendritic cells migration to draining LN is unaffected by antigen absorption and priming, which are affected by mitochondrial dysfunction. As per the views of the experts, there is a need for further studies on the Irg1/itaconate axis to explore the immunomodulatory role in dendritic cells effector function and Th2 inflammatory pathways driving asthma pathogenesis.

Moreover, Amarjit Mishra has drawn attention to the FAO pathway’s role in Th2 inflammation. Decreases in Th2 cytokine productions and Th2-associated airway hyperreactivity are brought on by these metabolic changes in ILC2.

He brought out the intriguing finding that the inhibitory axis of programmed cell death protein-1 (PD-1) functions as a metabolic checkpoint to suppress ILC2 proliferation and effector activity, including the release of pro allergenic cytokines IL25 and IL33. The importance of arginine metabolism, which is known to fuel Th2 inflammation, has also been highlighted by him.

In his assessment of the function of arginine, Amarjit Mishra found that earlier investigations on Arg2 defective mice had shown elevated STAT6 phosphorylation, increased IL13 secretion, and elevated eosinophilic airway inflammation. The production of Th2 cytokines including IL-5 and eotaxin-2 has also been demonstrated to be induced by arginine metabolism via HIF.

Alveolar macrophages, which express eotaxin-2 primarily, are important in eosinophilic infiltration of the airways. Moreover, Amarjit Mishra has concentrated on the significance of macrophage polarisation, which is known to be important in the pathophysiology of asthma.

One of the processes affected in the alveolar macrophages is the arachidonic acid pathway, according to a group of researchers led by Amarjit Mishra. Leukotrienes and prostaglandins are involved in the metabolism of arachidonic acid, which is released during asthma. Leukotrienes B4 and E4 have been found to be elevated in alveolar macrophages isolated from asthmatic patients.

This abnormal change in metabolism determines the progression of asthma through the pro-inflammatory effects of LTB4 that draw neutrophils and eosinophils into the airways and the bronchoconstrictive effects of LTE4 that result in effects like increased endothelial membrane permeability. The role of treating macrophages with octyl itaconate in suppressing M2 polarisation and JAK1 phosphorylation in vivo has also been investigated by the researchers.

The study’s findings have demonstrated the potential for metabolic changes to affect the phenotype of alveolar macrophages by affecting a number of transcription factors, metabolic pathways, and their intermediates, including itaconate. Alveolar macrophages exhibit metabolic plasticity in many phenotypes, which underscores the significance of comprehending the processes driving this variety.

Notably, the mouse lung does not resemble the milieu of a human lung with asthma. For instance, human asthmatic alveolar macrophages do not exhibit the elevation of Arg1 that is seen in murine models of alveolar macrophages. Nonetheless, the understanding of the metabolic control of macrophage polarisation provided by mouse models is significant and opens the door to the application of metabolic manipulation to drive changes in alveolar macrophage phenotype as a tool.



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