Neuroprotection by IFN-γ via astrocyte-secreted IL-6 in acute neuroinflammation

// Lijie Sun 1,2,* , Yan Li 1,2,* , Xiuzhi Jia 1,2,* , Qi Wang 1,2 , Yue Li 3 , Minghui Hu 4 , Linlu Tian 1,2 , Jinfeng Yang 1,2 , Wenjing Xing 1,2 , Weihua Zhang 5 , Jingtao Wang 6 , Hongwei Xu 1,2 , Lihua Wang 7 , Dekai Zhang 3 and Huan Ren 1,2 1 Department of Immunology, Harbin Medical University, Harbin, China 2 Key Laboratory of Infection & Immunity, Heilongjiang Province, Harbin, China 3 Center for Infectious and Inflammatory Disease, Institute of Biosciences and Technology, Texas A&M University System Health Science Center, Houston, TX, USA 4 Department of Clinical Laboratory, The Affiliated Hospital to Qingdao University, Qingdao, China 5 Department of Pathophysiology, Harbin Medical University, Harbin, China 6 Department of Epidemiology and Biostatistics, The Public Health Institute, Harbin Medical University, Harbin, China 7 Department of Neuroscience, The Second Hospital Affiliated to Harbin Medical University, Harbin, China Correspondence to: Huan Ren, email: // Dekai Zhang, email: // Lihua Wang, email: // Keywords : interferon-gamma, astrocyte, interleukin-6, apoptosis, neuroinflammation, Immunology and Microbiology Section, Immune response, Immunity Received : November 21, 2016 Accepted : March 22, 2017 Published : April 09, 2017 Abstract Inflammation eliminates pathogenic infections while also threatening the integrity of the central nervous system. In this study, using in vivo and in vitro models of acute neuroinflammation, we investigated the mechanisms by which inflammation and astrocytes affect neuronal apoptosis. The in vitro model mimicked acute neuroinflammation by incubation in IFN-γ-containing media with primary cultured cerebellar granule neurons, with or without cultured astrocytes. This quickly induced neuronal apoptosis characterized by cleaved caspase-3 expression, Hoechst 33342 staining, and intercellular Ca 2+ influx, whereas the presence of astrocytes significantly protected neurons from these effects. IFN-γ in the inflammation media also promoted astrocyte secretion of IL-6, essential for protection. The supernatants of rat peripheral blood mononuclear cells stimulated by lymphocyte mitogen lipopolysaccharide or concanavalin A were used as inflammation media to verify the results. The in vivo model involved a peripheral challenge with lipopolysaccharide, with or without recombinant IFN-γ, in C57BL/6 mice. This confirmed the in vitro results: anti-IFN-γ antibodies exacerbated the acute course of neuroinflammation and led to neurocyte apoptosis in vivo . The pro-inflammatory cytokine IFN-γ provided neuroprotection during acute neuroinflammation via induction of astrocyte-secreted IL-6. The findings provide novel insights into the mechanisms of neuroprotection by IFN-γ during acute neuroinflammation, and may impact therapies for inflammation-related central nervous system injury and disease.