STAT3 phosphorylation in the rheumatoid arthritis immunological synapse.

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Tác giả: Jesusa Capera, Michael L Dustin, Ashwin Jainarayanan, Hila Novak Kotzer, Joanne Macdonald, Viveka Mayya, Peter C Taylor, Salvatore Valvo, Alexandra Zanin-Zhorov

Ngôn ngữ: eng

Ký hiệu phân loại: 616.7227 *Diseases of musculoskeletal system

Thông tin xuất bản: United States : bioRxiv : the preprint server for biology , 2025

Mô tả vật lý:

Bộ sưu tập: NCBI

ID: 218109

Targeting the JAK/STAT pathway has emerged as a key therapeutic strategy for managing Rheumatoid Arthritis (RA). JAK inhibitors suppress cytokine-mediated signaling, including the critical IL-6/STAT3 axis, thereby effectively targeting different aspects of the pathological process. However, despite their clinical efficacy, a subset of RA patients remains refractory to JAK inhibition, underscoring the need for alternative approaches. Here, we identify a novel JAK-independent mechanism of STAT3 activation, which is triggered by the formation of the immunological synapse (IS) in naïve CD4+ T cells. Our data demonstrates that Lck mediates the TCR-dependent phosphorylation of STAT3 at the IS, highlighting this pathway as a previously unrecognized hallmark of early T cell activation. Furthermore, we show that the synaptic Lck/TCR-STAT3 pathway is compromised in RA. This discovery highlights a new therapeutic target for RA beyond JAK inhibitors, offering potential avenues for treating patients resistant to current therapies.
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