Modulation of autophagy via lentivirus-derived shAtg5 ameliorates lupus-like disease in mice

Abstract

Abstract Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by the production of anti-nuclear antibodies. Traditionally, immunosuppressive and cytotoxic agents were widely used to treat lupus. However, the side effect and toxicities are inevitable. Autophagy is a process which can degrade the aged organelles and unfolded proteins to maintain the cell homeostasis. Previous studies have shown that autophagy levels were positively correlated with disease severity and elevated in B and T cells of lupus-prone mice and lupus patients. Furthermore, autophagy is essential for plasma cell differentiation, survival and antibody production. These results implicate that autophagy may promote lupus progression through regulating the survival of autoreactive immune cells. Therefore, we aim to modulate the autophagy of lupus-prone mice by lentivirus-derived shRNA targeting Atg5, an essential protein for autophagy. First, we found that levels of autophagy in splenocytes and lymphocytes of peripheral blood (PB) were elevated and positively correlated with disease severity in lupus-prone mice. The shAtg5-lentivirus, which can effectively inhibit autophagy in vitro, were then i.p. injected into TREM-1−/−. lpr mice. Mice treated with shAtg5-lentivirus exhibited lower levels of proteinuria, serum anti-dsDNA antibody and B-cell activating factor (BAFF). Lymphadenopathy as well as autophagy levels in lymph node cells and PB lymphocytes were decreased following Atg5 suppression. We also found numbers of plasma cells, CD4−CD8−, and CD4+T cells were decreased in mice treated with shAtg5-lentivirus. Thus, inhibition of autophagy may suppress immune cell expansion in lupus-prone mice and provide a novel target therapy for SLE.