Background/Purpose: SOCS1 (suppressor of cytokine signaling 1) is a suppressor molecule of the JAK/STAT pathway and has been reported to be involved in the pathogenesis of SLE. T cell-specific or regulatory T cell (Treg)-specific Socs1-deficient mice exhibited lupus pathology with enhanced Treg plasticity, which rapidly lost the expression of Foxp3 through DNA hypermethylation of the Foxp3 promoter/enhancer and produced high levels of inflammatory cytokines (Takahashi R et al., J Immunol. 2017, Takahashi R et al., J Exp Med. 2011). In addition, loss-of-function mutant lineages of SOCS1 have recently been found to develop SLE and other diseases (Nature (2020, Nat Commun (2020)). In the present study, we examined whether the pathogenesis of SLE is suppressed in T-cell specific Socs1 transgenic (Socs1 Tg) mice.

Methods: Imiquimod cream was administered on the ear of age-matched 8-week-old female wild-type (WT) mice and Socs1 Tg mice every other day for up to 8 weeks, as reported previously. Pathological and immunological analyses of the spleen, lymph nodes, and kidneys of these mice were performed. Tregs and non-Tregs (CD4⁺CD25^– effector cells) from Socs1 Tg or WT mice with or without induction of lupus pathology were isolated using a cell sorter and analyzed. Peripheral blood lymphocytes of SLE patients were analyzed by gene transfer of Socs1.

Results: In the Socs1 Tg mice, the lupus-like phenotype was worse than when lupus was induced in WT mice by DNA antibody measurements and pathological analysis. To analyze those mechanisms, we first analyzed Treg function and found that in vitro, Tregs from Socs1 Tg mice had a more stable suppressive function than Tregs from WT mice, even under inflammatory conditions, by preventing plasticity. In vivo, in lupus-induced WT mice, Tregs from Socs1 Tg mice suppressed lupus pathology more potently than those from WT mice. Furthermore, similar experiments in lupus-induced Socs1 Tg mice showed that lupus pathology could not be suppressed with the same amount of Tregs derived from WT or Socs1 Tg mice as in lupus-induced WT mice, but could be suppressed by transplanting a sufficient amount of Tregs from Socs1 Tg mice. Next, analysis of non-Tregs in Socs1 Tg mice showed that they were activated and reduced in number in the spleen and lymph nodes, with cytokine production such as IL-17A, which was emphasized in the induction of lupus pathology. As a further cause of the reduction in non-Tregs, non-Tregs of Socs1 Tg mice were observed to decrease IL-7 receptor expression and increase apoptosis, which was accentuated in the induction of lupus pathology. Finally, Socs1 expression in peripheral blood lymphocytes of SLE patients did not show a characteristic relationship with lupus activity. However, transfection of Socs1 into lymphocytes from SLE patients promoted apoptosis in some patients but was not related to the production of IFNγ or IL-17A.

Conclusion: Both sustained up- or down-regulation of SOCS1 cause changes in CD4⁺ T cells through different mechanisms and exacerbate the pathogenesis of lupus. The importance of further exploring these pathological mechanisms to understand the dynamics of SOCS1 expression in SLE patients and to search for factors that regulate this dynamics is suggested.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/persistent-up-or-down-regulation-of-socs1-exacerbates-the-pathogenesis-of-systemic-lupus-erythematosus-through-several-mechanisms/