Type I interferons promote lupus through disruption of the lymphotoxin receptor-mediated mechanosensing MKL1 pathway in marginal zone macrophages (BA4P.124)

Abstract

Abstract Defective clearance of apoptotic cells (ACs) is a central pathogenic event in systemic lupus erythematosus (SLE). Here, we describe an underlying mechanism in which follicular translocation of marginal zone (MZ) B cells in the spleen of lupus BXD2 mice disrupts marginal zone macrophages (MZMs), which normally clear apoptotic debris and prevent entry of the AC antigens (AC-Ags) into the follicles. The phagocytosis of ACs by the spleen MZMs is enabled by a megakaryoblastic leukemia 1 (MKL1) transcription factor-mediated mechanosensing pathway. The MZ B cells maintain this pathway through their expression of membrane lymphotoxin-α1β2 (mLT). Follicular shuttling of mLT+ MZ B cells disengages their interaction with the LTβR+ MZMs, thereby downregulating MKL1 in the MZMs. This leads to defective F-actin polymerization, loss of their ability to clear ACs and eventually MZM dissipation. Type I interferon (IFN) signaling, a well-established clinical characteristic of SLE and is commonly considered as a downstream event of AC-Ag stimulation, is identified to play a key role in MZM erosion via promoting follicular shuttling of mLT+ B cells. Follicular translocation of MZ B cells, erosion of MZMs and loss of MKL1 were similarly identified in lupus B6.Sle1.Sle2.Sle3 mouse and human SLE spleens. Collectively, the results suggest that lupus might be interrupted by strategies that maintain or enhance mechanosensing signals in the MZM barrier to prevent follicular entry of AC-Ags.