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 KD 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. VISTA deficiency exacerbates
pristane-induced lupus-like disease in mice by promoting activation of the IFN-I and noncanonical NF-κB pathway.
Imatinib was screened as a small-molecule VISTA agonist by molecular docking, SPR, and cellular level experiments. VISTA agonists (M351-0056 and
imatinib) alleviated lupus-like
disease progression in the cGVHD mouse model and MRL/lpr mice by inhibiting activation of IFN-I and noncanonical NF-κB pathway.