Work

Splenocyte Apoptosis and Autophagy Is Mediated by Interferon Regulatory Factor 1 During Murine Endotoxemia

Year: 2012

Type: article

Abstract: In Brief Sepsis-induced lymphocyte and dendritic cell apoptosis contributes to immunosuppression, which results in an inability to eradicate the primary infection as well as a propensity to acquire new, secondary infections. Another cellular process, autophagy, is also activated in immune cells and plays a protective role. In the present study, we demonstrate that interferon regulatory factor 1 (IRF-1) regulates both immune cell apoptosis and autophagy in a murine endotoxemia model. Interferon regulatory factor 1 is activated at an early phase through a Toll-like receptor 4–dependent, myeloid differentiation primary response gene 88–independent manner in splenocytes. Furthermore, IRF-1 knockout (KO) mice are protected from a lethal endotoxemia model. This protection is associated with decreased apoptosis and increased autophagy in splenocytes. Interferon regulatory factor 1 KO mice experience decreased apoptotic cell loss, especially in CD4+ T lymphocytes and myeloid antigen-presenting cells. Meanwhile, IRF-1 KO mice demonstrate increased autophagy and improved mitochondrial integrity. This increased autophagy in KO mice is attributable, at least in part, to deactivation of mammalian target of rapamycin/P70S6 signaling—a main negative regulator of autophagy. Therefore, we propose a novel role for IRF-1 in regulating both apoptosis and autophagy in splenocytes in the setting of endotoxemia with IRF-1 promoting apoptosis and inhibiting autophagy. ABBREVIATION LPS—lipopolysaccharide; TLR4—Toll-like receptor 4; MyD88—myeloid differentiation primary response gene 88; TRIF—domain-containing adaptor inducing IFN-B; IRF-1—interferon regulatory factor 1; LC3—microtubule-associated protein 1 light chain 3; mTOR—mammalian target of rapamycin; WT—wild type; KO—knockout; APCs—antigen-presenting cells Splenocyte apoptotic and autophagic responses is mediated by IRF-1 in murine endotoxemia model.

Source: Shock

DOI: 10.1097/shk.0b013e318249cfa2