Abstract
Macrophage M2b polarization conferred by self-DNA immunization initiates and propagates lupus nephritis. Knockdown of DNA-dependent activator of interferon-regulatory factors (DAI) ameliorates SLE syndrome via blunting macrophage M2b polarization. DAI functions as a DNA sensor in self-DNA-induced macrophage M2b polarization and lupus nephritis. We disclose the mechanism by which self-DNA induces macrophage M2b polarization and lupus nephritis DNA-dependent activator of interferon-regulatory factors (DAI) functions as a cytoplasmic DNA sensor that activates the innate immune system. We previously found that activated lymphocyte-derived self-apoptotic DNA (ALD-DNA) immunization led to pathological macrophage activation and M2b polarization, which could initiate and propagate murine lupus nephritis. However, the specific DNA sensor(s) as well as underlying molecular mechanisms involved in ALD-DNA-induced macrophage M2b polarization in systemic lupus erythematosus (SLE) disease remains unknown. In this study, we reported that DAI expression was significantly increased in SLE patients as well as in lupus mice. Gain- and loss-of-function studies revealed that DAI was involved in ALD-DNA-induced macrophage activation and M2b polarization. Moreover, ALD-DNA notably induced dimerization/oligomerization of DAI and consequently activation of nuclear factor κB (NF-κB) and interferon regulatory factor 3 (IRF3) signaling pathways via calcium signaling, resulting in macrophage activation and M2b polarization. More importantly, blockade of DAI in vivo or selective knockdown of DAI in macrophages could ameliorate SLE syndrome via blunting macrophage M2b polarization and inhibiting inflammatory response in lupus mice. Our results suggest that DAI could function as a DNA sensor and a regulator in ALD-DNA-induced macrophage M2b polarization and lupus nephritis, providing the possible molecular mechanisms involved in ALD-DNA-induced macrophage M2b polarization in SLE disease and making DAI as a potential therapeutic target for the treatment of SLE.
Highlights
Macrophage M2b polarization conferred by self-DNA immunization initiates and propagates lupus nephritis
dependent activator of interferon-regulatory factors (DAI) Expression Is Significantly Increased in systemic lupus erythematosus (SLE) Patients as well as in Lupus Mice—To investigate whether DAI was involved in SLE disease, real-time PCR analysis was performed to detect the levels of DAI in peripheral blood mononuclear cell (PBMC) of SLE patients and the matched controls
As lupus nephritis was a major cause of morbidity in SLE patients, kidney tissues were selected to analyze the expression of DAI in dendritic cells, macrophages, T cells, and B cells
Summary
Macrophage M2b polarization conferred by self-DNA immunization initiates and propagates lupus nephritis. We previously found that activated lymphocyte-derived self-apoptotic DNA (ALD-DNA) immunization led to pathological macrophage activation and M2b polarization, which could initiate and propagate murine lupus nephritis. Our results suggest that DAI could function as a DNA sensor and a regulator in ALD-DNA-induced macrophage M2b polarization and lupus nephritis, providing the possible molecular mechanisms. Further study demonstrated that ALD-DNA immunization led to macrophage infiltration and aberrant activation and M2b polarization in murine renal tissues, which mediated the onset and aggravation of SLE disease [25, 26], suggesting that ALD-DNA-induced aberrant activation and M2b polarization of macrophage plays a crucial pathogenic role in ALD-DNA-mediated lupus nephritis and autoimmune response. ALD-DNA could induce the dimerization/oligomerization of DAI and activate DAI signaling pathways via regulating calcium signaling, resulting in macrophage aberrant activation and lupus nephritis, implying the possible mechanisms for the recognition and regulation of ALD-DNA-induced pathological macrophage activation in the context of SLE disease
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