Original Article

Citation: Cell Death and Disease (2015) 6, e1702; doi:10.1038/cddis.2015.69
Published online 26 March 2015

Induction of COX-2-PGE2 synthesis by activation of the MAPK/ERK pathway contributes to neuronal death triggered by TDP-43-depleted microglia
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Q Xia1, Q Hu1, H Wang1, H Yang1, F Gao1, H Ren1, D Chen1, C Fu2, L Zheng1, X Zhen1, Z Ying1,3 and G Wang1,2

  1. 1Laboratory of Molecular Neuropathology, Jiangsu Key Laboratory of Translational Research and Therapy for Neuro-Psycho-Diseases and College of Pharmaceutical Sciences, Soochow University, Suzhou, Jiangsu, China
  2. 2Key Laboratory of Brain Function and Disease, School of Life Sciences, University of Science & Technology of China, Chinese Academy of Sciences, Hefei, Anhui, China
  3. 3Jiangsu Key Laboratory of Preventive and Translational Medicine for Geriatric Diseases, College of Pharmaceutical Sciences, Soochow University, Suzhou, Jiangsu, China

Correspondence: Z Ying or G Wang, Laboratory of Molecular Neuropathology, Jiangsu Key Laboratory of Translational Research and Therapy for Neuro-Psycho-Diseases and College of Pharmaceutical Sciences, Soochow University, Suzhou 215021, Jiangsu, China. Tel: +86 512 65884845; Fax: +86 512 65884845; E-mail: zheng.ying@suda.edu.cn or wanggh@suda.edu.cn

Received 24 October 2014; Revised 17 January 2015; Accepted 16 February 2015

Edited by A Verkhratsky

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Abstract

Neuroinflammation is a striking hallmark of amyotrophic lateral sclerosis (ALS) and other neurodegenerative disorders. Previous studies have shown the contribution of glial cells such as astrocytes in TDP-43-linked ALS. However, the role of microglia in TDP-43-mediated motor neuron degeneration remains poorly understood. In this study, we show that depletion of TDP-43 in microglia, but not in astrocytes, strikingly upregulates cyclooxygenase-2 (COX-2) expression and prostaglandin E2 (PGE2) production through the activation of MAPK/ERK signaling and initiates neurotoxicity. Moreover, we find that administration of celecoxib, a specific COX-2 inhibitor, greatly diminishes the neurotoxicity triggered by TDP-43-depleted microglia. Taken together, our results reveal a previously unrecognized non-cell-autonomous mechanism in TDP-43-mediated neurodegeneration, identifying COX-2-PGE2 as the molecular events of microglia- but not astrocyte-initiated neurotoxicity and identifying celecoxib as a novel potential therapy for TDP-43-linked ALS and possibly other types of ALS.

Abbreviations:

ALS, amyotrophic lateral sclerosis; AD, Alzheimer’s disease; COX-2, cyclooxygenase-2; DMSO, dimethyl sulfoxide; EGFP, enhanced green fluorescent protein; FBS, fetal bovine serum; GAPDH, glyceraldehyde-3-phosphate dehydrogenase; FTLD, frontotemporal lobar degeneration; MAPK, mitogen-activated protein kinase; PGE2, prostaglandin E2; PD, Parkinson’s disease; qRT-PCR, quantitative real-time PCR; siRNA, small interfering RNA; SOD1, Cu/Zn superoxide dismutase 1; TARDBP, TAR DNA-binding protein 43