Progranulin Controls Sepsis via C/EBPα-Regulated Il10 Transcription and Ubiquitin Ligase/Proteasome-Mediated Protein Degradation.
Progranulin (PGRN) is a widely expressed, pleiotropic protein that is involved in diverse biological processes, including cellular proliferation, neuron development, and wound healing. However, the role of PGRN in the regulation of pathogen-induced systemic inflammation and the mechanisms involved have not been established. In this study, we show that PGRN-deficient mice display heightened mortality in models of polymicrobial sepsis and endotoxinemia, with increased tissue levels of inflammatory cytokines and reduced IL-10 production. Conversely, administration of rPGRN decreases the susceptibility of PGRN-deficient mice to LPS-induced endotoxemic shock and augments IL-10 production by LPS-activated macrophages in a TNFR-dependent manner. Molecular analysis reveals a direct role of the transcription factor C/EBPα in PGRN-regulated IL-10 expression. C/EBPα-deficient macrophages produce less IL-10 in response to LPS. Furthermore, mice deficient in C/EBPα in hematopoietic cells are highly vulnerable to LPS-induced septic shock. Lastly, the defective IL-10 production by PGRN-deficient cells is primarily due to reduced C/EBPα protein stability via the E3 ubiquitin-conjugating enzyme E6AP and proteasome-mediated degradation. To our knowledge, this study provides the first evidence that PGRN is a nonredundant regulator of systemic inflammation via modulating the levels and activity of C/EBPα, IL-10, and the ubiquitin-proteasome proteolysis pathway. The results bear strong and profound implications for PGRN insufficiency and its mutation-associated systemic and organ-specific inflammatory human diseases.
State Key Laboratory of Microbial Metabolism, Sheng Yushou Center of Cell Biology and Immunology, School of Life Science and Biotechnology, Shanghai Jiao Tong University, Shanghai 200240, China.
Wenjun
0000-0003-1938-1782
W
Yan
Department of Microbiology and Immunology, Weill Cornell Medical College, New York, NY 10065; and.
Aihao
0000-0002-9152-2984
A
Ding
Department of Physiology, Kyungpook National University School of Medicine, Jung-gu, Daegu 41944, Republic of Korea.
Ha-Jeong
0000-0002-7341-7988
HJ
Kim
State Key Laboratory of Microbial Metabolism, Sheng Yushou Center of Cell Biology and Immunology, School of Life Science and Biotechnology, Shanghai Jiao Tong University, Shanghai 200240, China.
Hua
H
Zheng
State Key Laboratory of Microbial Metabolism, Sheng Yushou Center of Cell Biology and Immunology, School of Life Science and Biotechnology, Shanghai Jiao Tong University, Shanghai 200240, China.
Fang
F
Wei
State Key Laboratory of Microbial Metabolism, Sheng Yushou Center of Cell Biology and Immunology, School of Life Science and Biotechnology, Shanghai Jiao Tong University, Shanghai 200240, China; xim2002@med.cornell.edu.|Department of Microbiology and Immunology, Weill Cornell Medical College, New York, NY 10065; and.
Xiaojing
X
Ma
D000818:Animals; D022763:CCAAT-Enhancer-Binding Protein-alpha / Q000378:metabolism*; D000077155:Granulins; D036341:Intercellular Signaling Peptides and Proteins / Q000172:deficiency / Q000378:metabolism*; D016753:Interleukin-10 / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D000077153:Progranulins; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism*; D059748:Proteolysis; D018805:Sepsis / Q000378:metabolism*; D044763:Ubiquitin-Conjugating Enzymes / Q000378:metabolism*
D022763:CCAAT-Enhancer-Binding Protein-alpha; D000077155:Granulins; C120204:Grn protein, mouse; C556062:IL10 protein, mouse; D036341:Intercellular Signaling Peptides and Proteins; D000077153:Progranulins; D016753:Interleukin-10; D044763:Ubiquitin-Conjugating Enzymes; D046988:Proteasome Endopeptidase Complex