• the Korean Society for Brain and Neural Sciences


Original Article

Exp Neurobiol 2022; 31(5): 307-323

Published online October 31, 2022

© The Korean Society for Brain and Neural Sciences

Lipopolysaccharide-induced Autophagy Increases SOX2-positive Astrocytes While Decreasing Neuronal Differentiation in the Adult Hippocampus

Wen-Chung Liu1,2†, Chih-Wei Wu1,3†, Mu-Hui Fu4, You-Lin Tain5,6,7, Chih-Kuang Liang8, I-Chun Chen5, Chun-Ying Hung5, Yu-Chi Lee5 and Kay L.H. Wu5,9*

1Department of Plastic Surgery, Kaohsiung Veterans General Hospital, Kaohsiung 813414, 2Department of Surgery, School of Medicine, National Yang Ming Chiao Tung University, Taipei 112034, 3Department of Counseling, National Chia-Yi University, Chia-Yi 621, 4Department of Neurology, Kaohsiung Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Kaohsiung 83301, 5Institute for Translational Research in Biomedicine, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung 83301, 6Department of Pediatrics, Kaohsiung Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Kaohsiung 83301, 7College of Medicine, Chang Gung University, Taoyuan 330, 8Center for Geriatrics and Gerontology, Division of Neurology, Kaohsiung Veterans General Hospital, Kaohsiung 813414, 9Department of Senior Citizen Services, National Tainan Institute of Nursing, Tainan 700, Republic of China

Correspondence to: *To whom correspondence should be addressed.
TEL: 886-7-7317123 (ext. 8596), FAX: 886-7-7317123 (ext. 8569)
These authors contributed equally to this article.

Received: January 27, 2022; Revised: September 28, 2022; Accepted: October 9, 2022

This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License ( which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

Inflammation alters the neural stem cell (NSC) lineage from neuronal to astrogliogenesis. However, the underlying mechanism is elusive. Autophagy contributes to the decline in adult hippocampal neurogenesis under E. coli lipopolysaccharide (LPS) stimulation. SRY-box transcription Factor 2 (SOX2) is critical for NSC self-renewal and proliferation. In this study, we investigated the role of SOX2 in induced autophagy and hippocampal adult neurogenesis under LPS stimulation. LPS (5 ng•100 g-1•hour-1 for 7 days) was intraperitoneally infused into male Sprague–Dawley rats (8 weeks old) to induce mild systemic inflammation. Beclin 1 and autophagy protein 12 (Atg12) were significantly upregulated concurrent with decreased numbers of Ki67- and doublecortin (DCX)-positive cells in the dentate gyrus. Synchronically, the levels of phospho(p)-mTOR, the p-mTOR/mTOR ratio, p-P85s6k, and the p-P85s6k/P85s6k ratio were suppressed. In contrast, SOX2 expression was increased. The fluorescence micrographs indicated that the colocalization of Beclin 1 and SOX2 was increased in the subgranular zone (SGZ) of the dentate gyrus. Moreover, increased S100β-positive astrocytes were colocalized with SOX2 in the SGZ. Intracerebroventricular infusion of 3-methyladenine (an autophagy inhibitor) effectively prevented the increases in Beclin 1, Atg12, and SOX2. The SOX2+-Beclin 1+ and SOX2+-S100β+ cells were reduced. The levels of p-mTOR and p-P85s6k were enhanced. Most importantly, the number of DCX-positive cells was preserved. Altogether, these data suggest that LPS induced autophagy to inactivate the mTOR/P85s6k pathway, resulting in a decline in neural differentiation. SOX2 was upregulated to facilitate the NSC lineage, while the autophagy milieu could switch the SOX2-induced NSC lineage from neurogenesis to astrogliogenesis.

Graphical Abstract

Keywords: Autophagy, SOX2, mTOR signaling, Adult hippocampal neurogenesis, Lipopolysaccharide