In:
The Journal of Immunology, The American Association of Immunologists, Vol. 207, No. 12 ( 2021-12-15), p. 2933-2943
Kurzfassung:
Autoimmune uveitis (AU) is a sight-threatening ocular inflammatory disorder, characterized by massive retinal vascular leakage and inflamed lesions with infiltration of the uveitogenic T cells in the retina and disorders of the T cell–related immune response in the system. Stimulation of TCRs can trigger calcium release and influx via Ca2+ channels and then transmit signals from the surface to the nucleus, which are important for energy metabolism, proliferation, activation, and differentiation. Inhibition of Ca2+ influx by pharmacological modulation of Ca2+ channels may suppress T cell function, representing a novel anti-inflammatory strategy in the treatment of AU. This study investigated the effects of the l-type voltage-gated calcium channel blocker nimodipine in experimental AU (EAU). Nimodipine was found to not only decrease the clinical and histopathological inflammation score of EAU (C57BL/6J mice) but also dwindle the infiltration of uveitogenic CD4+ T cells into the retina. Moreover, nimodipine decreased the effector T cells and increased the regulatory T cells in the immune system. In vitro, nimodipine reduced the effector T cell differentiation of the IRBP1–20–specific CD4+ T cells of EAU mice and LPS-stimulated PBMCs of uveitis patients. Meanwhile, nimodipine suppressed the energy metabolism, proliferation, activation, and Th1 cell differentiation of T cells. Further studies on RNA sequencing and molecular mechanisms have established that nimodipine alleviates EAU by regulating T cells response through the p38–MAPK pathway signaling. Taken together, our data reveal a novel therapeutic potential of the l-type Ca2+ channels antagonist nimodipine in AU by regulating the balance of T cell subsets.
Materialart:
Online-Ressource
ISSN:
0022-1767
,
1550-6606
DOI:
10.4049/jimmunol.2100568
Sprache:
Englisch
Verlag:
The American Association of Immunologists
Publikationsdatum:
2021
ZDB Id:
1475085-5
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