Connection between JAK/STAT and PPARγ Signaling During the Progression of Multiple Sclerosis: Insights into the Modulation of T-Cells and Immune Responses in the Brain

(E-pub Ahead of Print)

Author(s): Nitish Kumar, Nidhi Sharma, Sidharth Mehan*

Journal Name: Current Molecular Pharmacology


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Abstract:

Multiple Sclerosis (MS) is a severe brain and spinal cord condition with a diverse autoimmune response and a wide variety of demyelination symptoms that primarily affect young adults. The primary reason for this disease is inflammation of white and grey matter caused by increased production of proinflammatory cytokines, which further damages the progenitor oligodendrocytes and appears to induce hypertrophy of the astrocytes and gliosis. Overexpression of the JAK/STAT signaling pathway contributes directly to physiological and pathological results in motor neuron diseases. Cytokines such as IL-17, IL-6, IL-12, TNF-α, and INF-ϒ use JAK/STAT signaling to trigger self-reactive CD4+ T-cells and differentiate them into Th1 phenotypes that overactivate immune reactions in the brain. Similarly, PPARγ plays a critical role in regulating the immune response by providing an anti-inflammatory effect by inhibiting macrophage and cytokine production activation. PPARγ also mediates the intrinsic molecular process of the T-cell, which selectively regulates the differentiation of Th17. Various studies indicate the neuroprotective function of PPARγ agonists by attenuating the JAK/STAT mediated activation of glial cells, inhibiting interleukin, and the differentiation of Th1 cells. Therefore, to maintain the brain's immune system, both PPARγ and JAK/STAT oppositely regulate each other. Dysregulation in JAK/STAT and PPARγ signaling contributes to several physiological changes leading to neurological disorders, including MS. Based on the above view, we have summarized the combined role of JAK/STAT-PPARγ signaling in MS and explored potential therapeutic strategies for disease improvement by the use of pathway modulators.

Keywords: Multiple sclerosis, JAK/STAT, PPARγ, demyelination, oligodendrocytes, immunity, cytokines, glial cells, interleukins.

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Article Details

Published on: 01 March, 2021
(E-pub Ahead of Print)
DOI: 10.2174/1874467214666210301121432
Price: $95

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