Interferon-induced mechanosensing defects impede apoptotic cell clearance in lupus
Hao Li, … , Hui-Chen Hsu, John D. Mountz
Hao Li, … , Hui-Chen Hsu, John D. Mountz
Published June 22, 2015
Citation Information: J Clin Invest. 2015;125(7):2877-2890. https://doi.org/10.1172/JCI81059.
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Research Article Autoimmunity Immunology

Interferon-induced mechanosensing defects impede apoptotic cell clearance in lupus

Abstract

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.

Authors

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

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Figure 7

Follicular translocation of MZ B cells and decreased expression of MKL1 in lupus B6.TC mouse and human SLE spleens.

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Follicular translocation of MZ B cells and decreased expression of MKL1 ...
(A and B) Spleens obtained from B6 and B6.TC mice at the indicated ages were analyzed. (A) Confocal microscopic images of mLT, CD138, and MARCO for a representative splenic follicle from each group. Original magnification, ×20. (B) Confocal microscopic images of MARCO, PNA, and MKL1 for a representative splenic follicle from each group. Original magnification, ×20. Boxed areas in the left 4 panels are shown digitally magnified in the right 4 panels. Bar graphs show quantitation of the relative percentage of mLT+ cells that were in the MZ (A) or the percentage of MARCO+ cells that were also MKL1+ (B). At least 10 randomly chosen areas were counted per follicle, and 3–5 follicles were analyzed for each spleen. All data represent the mean ± SEM (#P < 0.01, §P < 0.005 vs. B6; n = 3–4 mice from each group). (C and D) IHC staining of CD1c+ MZ B cells (C) and MKL1 (D) in paraffin-embedded spleen sections derived from normal individuals (n = 6) and patients with SLE (n = 5). Original magnification, ×20. Boxed areas are shown digitally magnified on the right. ImageJ intensity quantitation of 10 randomly selected splenic perifollicular regions per section is shown on the right. Data represent the mean ± SEM (#P < 0.01, §P < 0.005 vs. B6 mice or non-SLE controls, Student’s t test).