Abstract
The increased death of macrophages has been considered as a pathogenic factor for systemic lupus erythematosus (SLE), and dysfunction of autophagy may contribute to improper cell death. However, the effect of autophagy on macrophage during the pathogenesis of SLE is still unclear. Here we found that the death rate and autophagy level of macrophages significantly increased in MRL/lpr lupus-prone mice. Activation of toll-like receptor 7 (TLR7) triggered macrophage death in an autophagy-dependent but caspase-independent way in vitro. Moreover, P62/SQSTM1 is thought to have an essential role in selective autophagy. We also demonstrated that P62/SQSTM1 was required for TLR7-induced autophagy, and knockdown of P62 suppressed R848-induced cell death and LC3II protein accumulation. As an important mediator for cell–cell communication, Notch signaling is responsible for cell-fate decisions. Our results showed that activation of TLR7 also upregulated the expression of Notch1, especially its downstream target gene Hairy and enhancer of split 1 (Hes-1) in macrophages. Of note, we found that Hes-1, as a transcriptional factor, controlled TLR7-induced autophagy by regulating P62 expression. Furthermore, to confirm the above results in vivo, TLR7 agonist imiquimod (IMQ)-induced lupus mouse model was prepared. Splenic macrophages from IMQ-treated mice exhibited increased autophagy and cell death as well as enhanced expressions of Notch1 and Hes-1. Our results indicate that Notch1-Hes-1 signaling controls TLR7-induced autophagic death of macrophage via regulation of P62 in mice with lupus.
Highlights
Systemic lupus erythematosus (SLE) is a typical autoimmune disease with heterogeneous clinical presentations including skin rash, glomerulonephritis and leukopenia.[1]
These results indicate that macrophages in lupus mice displayed increased expression of TLR7, elevated death and enhanced autophagy
It was reported that patients with SLE had increased apoptotic macrophage,[7,8] which may lead to defect in clearance of apoptotic cells and accelerate autoimmune disorders.[9]
Summary
Systemic lupus erythematosus (SLE) is a typical autoimmune disease with heterogeneous clinical presentations including skin rash, glomerulonephritis and leukopenia.[1]. TLR7-deficient lupus-prone mice showed decreased lymphocyte activation and ameliorated disease symptoms.[20,21] In contrast, wild-type mice treated with TLR7 agonists developed severe systemic autoimmunity.[22] Our previous studies revealed a pathogenic role of TLR7 in SLE.[23,24] It was reported that TLR7 could detect single-stranded RNA and eliminate intracellular pathogens by inducing autophagy.[25] In particular, some studies have indicated that P62/SQSTM1 has an essential role in selective autophagy induced by various stressors.[26]. P62/SQSTM1 is a member of sequestasome-like receptors, which acts as an adaptor by directly binding ubiquitinated bacteria (or probably viruses) and targeting them to autophagosomes.[27,28] the role of P62 in Received 12.3.16; revised 11.7.16; accepted 12.7.16; Edited by E Baehrecke
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