Abstract: Objective To clarify the regulatory effect of DNA released by apoptotic multiple myeloma cells on the antiviral innate immunity of macrophages, and to elucidate its molecular mechanism, to provide experimental evidence for understanding the immunological mechanism underlying the high susceptibility to viral infections in patients with multiple myeloma. Methods Human RPMI-8226 cells were induced to undergo apoptosis by ultraviolet irradiation. The apoptotic conditioned medium (Apo-CM) was collected to treat THP-1 macrophages, followed by VSV-GFP virus infection. Viral replication, as well as the expression levels of IFN-β, IL-6 and VSV-G were detected by fluorescence microscopy and quantitative real-time PCR (qPCR). DNase Ⅰ and RNase A were used to treat Apo-CM to identify the key effector molecules. Specific inhibitors targeting cGAS, STING and TLR9 were applied to block the corresponding pathways for further exploration of the immune regulatory mechanism. Results Preconditioning with Apo-CM markedly promoted viral replication and suppressed IFN-β secretion in macrophages, and such immunosuppressive effects were enhanced in a time-dependent manner (P＜0.05). Degradation of DNA by DNase Ⅰ significantly reversed the immunosuppressive effect of Apo-CM(P＜0.01), while RNase A treatment exerted no obvious influence. ConclusionsDNA derived from apoptotic myeloma cells inhibits the type Ⅰ interferon response and impairs antiviral innate immunity in macrophages through activating the TLR9 and cGAS-STING pathways, thereby facilitating viral replication.

Key words: multiple myeloma, cyclic GMP-AMP synthase(cGAS), STING, Toll-like receptor 9(TLR9), antiviral immunity