The autoimmune disease systemic lupus erythematosus (SLE) is characterized by increased type I IFN and circulating apoptotic cell-derived autoantigens (AC-Ags), both of which drive autoantibody production by B cells. In this episode, John Mountz, Hui-Chen Hsu, and Hao Li describe a mechanism by which type 1 IFN prevents clearance of ACs by marginal zone macrophages (MZMs) in SLE. The authors found that in murine SLE models, type I IFN increased follicular translocation of MZ B cells in the spleen, which disrupted the interaction between these B cells and MZ macrophages (MZMs). The interaction between MZ B cells and MZMs was shown to activate the megakaryoblastic leukemia 1–mediated (MKL1-mediated) mechanosensing pathway, which was essential for MZMs to phagocytize ACs and thereby prevent follicular entry of AC-Ags. Moreover, these defects were also present in spleens from patients with SLE. The results of this study suggest that strategies to maintain this mechanosensing pathway may block follicular entry of AC-Ags and prevent the development of autoantibodies against these antigens.
Systemic lupus erythematosus (SLE) is a severe autoimmune disease that is associated with increased circulating apoptotic cell autoantigens (AC-Ags) as well as increased type I IFN signaling. Here, we describe a pathogenic mechanism in which follicular translocation of marginal zone (MZ) B cells in the spleens of BXD2 lupus mice disrupts marginal zone macrophages (MZMs), which normally clear AC debris and prevent follicular entry of AC-Ags. Phagocytosis of ACs by splenic MZMs required the megakaryoblastic leukemia 1 (MKL1) transcriptional coactivator–mediated mechanosensing pathway, which was maintained by MZ B cells through expression of membrane lymphotoxin-α1β2 (mLT). Specifically, type I IFN–induced follicular shuttling of mLT-expressing MZ B cells disengaged interactions between these MZ B cells and LTβ receptor–expressing MZMs, thereby downregulating MKL1 in MZMs. Loss of MKL1 expression in MZMs led to defective F-actin polymerization, inability to clear ACs, and, eventually, MZM dissipation. Aggregation of plasmacytoid DCs in the splenic perifollicular region, follicular translocation of MZ B cells, and loss of MKL1 and MZMs were also observed in an additional murine lupus model and in the spleens of patients with SLE. Collectively, the results suggest that lupus might be interrupted by strategies that maintain or enhance mechanosensing signaling in the MZM barrier to prevent follicular entry of AC-Ags.
Hao Li, Yang-Xin Fu, Qi Wu, Yong Zhou, David K. Crossman, PingAr Yang, Jun Li, Bao Luo, Laurence M. Morel, Janusz H. Kabarowski, Hideo Yagita, Carl F. Ware, Hui-Chen Hsu, John D. Mountz