V-domain immunoglobulin suppressor of T-cell activation (VISTA), an important negative checkpoint protein, participates in immunoregulation. Systemic lupus erythematosus (SLE) is an autoimmune disease in which patients exhibit high levels of autoantibodies and multi-organ tissue injury, primarily involving the kidney and skin. In wild-type (WT) mice and Vsir^-/- mice with pristane-induced lupus-like disease, we found that VISTA deficiency exacerbated the lupus-like disease in mice, possibly through aberrant activation of type I interferon (IFN-I) signaling, CD4⁺ T cell, and noncanonical nuclear factor-κB (NF-κB) pathway. Surface plasmon resonance results showed that imatinib, an FDA-approved tyrosine kinase inhibitor, may have a high affinity for human VISTA-ECD with a K_D value of 0.2009 μM. The biological activities of imatinib and VISTA agonist M351-0056 were studied in monocytes and T cells and in lupus-like disease murine model of chronic graft-versus-host disease (cGVHD) and lupus-prone MRL/lpr mice. VISTA small-molecule agonist reduced the cytokine production of peripheral blood mononuclear cells (PBMCs) and Jurkat cells and inhibited PBMCs proliferation. Moreover, they attenuated the levels of autoantibodies, renal injury, inflammatory cytokines, chemokines, and immune cell expansion in the cGVHD mouse model and MRL/lpr mice. Our findings also demonstrated that VISTA small-molecule agonist ameliorated the development of SLE through improving aberrantly activated IFN-I signaling and noncanonical NF-κB pathway. In conclusion, VISTA has a protective effect on the development and progression of SLE. VISTA agonist M351-0056 and imatinib have been firstly demonstrated to attenuate SLE, suggesting interventions to enhance VISTA function may be effective in treating SLE.

Graphical abstract

中文翻译：

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伊马替尼和 M351-0056 通过 IFN-I 和非经典 NF-κB 途径增强 VISTA 功能并改善 SLE 的发展

V 域 T 细胞激活免疫球蛋白抑制蛋白 (VISTA) 是一种重要的阴性检查点蛋白，参与免疫调节。系统性红斑狼疮 (SLE) 是一种自身免疫性疾病，患者表现出高水平的自身抗体和多器官组织损伤，主要累及肾脏和皮肤。在患有降植烷诱导的狼疮样疾病的野生型 (WT) 小鼠和 Vsir -/- 小鼠中，我们发现 VISTA 缺乏可能通过 I 型干扰素 (IFN-I) 的异常激活加剧了小鼠的狼疮样^疾病信号传导、CD4 ⁺ T 细胞和非经典核因子-κB (NF-κB) 通路。表面等离子共振结果显示，FDA批准的酪氨酸激酶抑制剂伊马替尼可能与人VISTA-ECD具有高亲和力，K _D值为0.2009 μM。在单核细胞和 T 细胞以及慢性移植物抗宿主病 (cGVHD) 的狼疮样疾病小鼠模型和易患狼疮的 MRL/lpr 小鼠中研究了伊马替尼和 VISTA 激动剂 M351-0056 的生物活性。VISTA小分子激动剂减少外周血单核细胞（PBMC）和Jurkat细胞的细胞因子产生，并抑制PBMC增殖。此外，它们还降低了 cGVHD 小鼠模型和 MRL/ lpr小鼠的自身抗体、肾损伤、炎症细胞因子、趋化因子和免疫细胞扩增的水平。我们的研究结果还表明，VISTA 小分子激动剂通过改善异常激活的 IFN-I 信号传导和非经典 NF-κB 通路来改善 SLE 的发展。总之，VISTA对SLE的发生和进展具有保护作用。VISTA 激动剂 M351-0056 和伊马替尼已首次被证明可以减轻 SLE，这表明增强 VISTA 功能的干预措施可能有效治疗 SLE。

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