Blockade of Notch1 signaling alleviates murine lupus via blunting macrophage activation and M2b polarization

W Zhang, W Xu, S Xiong - The Journal of Immunology, 2010 - journals.aai.org
W Zhang, W Xu, S Xiong
The Journal of Immunology, 2010journals.aai.org
Patients with systemic lupus erythematosus (SLE) are found to be accompanied with innate
immunity dysregulation including abnormally macrophage activation. But the functional
polarization of the activated macrophages and its underlying molecular mechanism during
the pathogenesis of SLE remains unknown. As an important local cellular interaction
mechanism responsible for cell fate determination, Notch signaling is reported to exert
crucial functions in the development and differentiation of various immunocytes, whereas its …
Abstract
Patients with systemic lupus erythematosus (SLE) are found to be accompanied with innate immunity dysregulation including abnormally macrophage activation. But the functional polarization of the activated macrophages and its underlying molecular mechanism during the pathogenesis of SLE remains unknown. As an important local cellular interaction mechanism responsible for cell fate determination, Notch signaling is reported to exert crucial functions in the development and differentiation of various immunocytes, whereas its role in macrophage polarization is not fully understood. In this study, in the SLE murine model generated by immunization with activated lymphocyte-derived DNA (ALD-DNA), infiltrated macrophages in the nephritic tissues were found to exhibit activation and M2b functional polarization. Notch1 signaling activity was significantly upregulated in the ALD-DNA–induced M2b macrophages in vitro and in vivo. Furthermore, ALD-DNA–induced M2b polarization was found to be dependent on enhanced Notch1 signaling through accelerating NF-κB p50 translocation into the nucleus mediated by PI3K and MAPK pathways. Moreover, blockade of Notch1 signaling with γ-secretase inhibitor treatment before or after the disease initiation could ameliorate murine lupus through impeding macrophage M2b polarization. Our results implied that Notch1 signaling-dependent macrophage M2b polarization might play a pivotal role in the pathogenesis of SLE, which could provide Notch1 signaling blockade as a potential therapeutic approach for SLE disease.
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