Interferon-induced mechanosensing defects impede apoptotic cell clearance in lupus

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

Research output: Contribution to journalArticle

32 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)2877-2890
Number of pages14
JournalJournal of Clinical Investigation
Volume125
Issue number7
DOIs
StatePublished - Jul 1 2015

ASJC Scopus subject areas

  • Medicine(all)

Fingerprint Dive into the research topics of 'Interferon-induced mechanosensing defects impede apoptotic cell clearance in lupus'. Together they form a unique fingerprint.

  • Cite this

    Li, H., Fu, Y. X., Wu, Q., Zhou, Y., Crossman, D. K., Yang, P., Li, J., Luo, B., Morel, L. M., Kabarowski, J. H., Yagita, H., Ware, C. F., Hsu, H. C., & Mountz, J. D. (2015). Interferon-induced mechanosensing defects impede apoptotic cell clearance in lupus. Journal of Clinical Investigation, 125(7), 2877-2890. https://doi.org/10.1172/JCI81059