Identification of Caspase-6 as a New Regulator of Alternatively Activated Macrophages.
Alternatively activated macrophages (AAMs) play essential roles in the promotion of tissue remodeling, vasculogenesis, and tumor progression; however, the detailed mechanisms underlying the activation of AAMs remain largely unknown. Here, by using quantitative proteomic analysis, we identified 62 proteins that were up-regulated in IL-4-induced macrophages. Among these, Caspase-6 was increased significantly. Caspase-6 is important in the apoptotic signaling pathway; however, its role in non-apoptosis is also reported. Here, we first examined the non-apoptotic role of Caspase-6 in the alternative activation of macrophages after administration of IL-4, 4T1 tumor conditional medium, or co-culture with 4T1 cells. Both treatments promoted alternative activation of RAW264.7 cells and primary macrophages, whereas disruption of caspase-6 expression and activity could markedly suppress the biomarker levels of AAMs. Overexpression of Caspase-6 could significantly promote the activation of AAMs. Importantly, we further present evidence that caspase-6 could regulate breast cancer cell invasion by modulating MMP-2 and MMP-9 expression in 4T1 tumor-associated macrophages, as ablation of protein levels or activity of caspase-6 suppressed tumor cell invasion in vitro In conclusion, the observed results markedly expanded our views of the dynamic changes in protein composition during alternative activation of macrophages, and they revealed a critical new role of caspase-6 in regulating this cellular biological process, which suggested that caspase-6 might be a key nod molecule to regulate immunological steady-state and be a therapeutic candidate for tumor immunotherapy.
From the State Key Laboratory of Pharmaceutical Biotechnology and MOE Key Laboratory of Model Animal for Disease Study, Model Animal Research Center, Nanjing University, Nanjing 210023, China.
Yongfang
Y
Yao
the Division of Nephrology, Department of Medicine, University of Texas Health Science Center at San Antonio, San Antonio, Texas 78229.
Qian
Q
Shi
the Department of Hematology, Nanjing Drum Tower Hospital, Nanjing University Medical School, Nanjing 210008, China, and.
Bing
B
Chen
the State Key Laboratory of Protein and Plant Gene Research, College of Life Sciences, Peking University, Beijing 100871, China.
Qingsong
Q
Wang
From the State Key Laboratory of Pharmaceutical Biotechnology and MOE Key Laboratory of Model Animal for Disease Study, Model Animal Research Center, Nanjing University, Nanjing 210023, China.
Xinda
X
Li
From the State Key Laboratory of Pharmaceutical Biotechnology and MOE Key Laboratory of Model Animal for Disease Study, Model Animal Research Center, Nanjing University, Nanjing 210023, China.
Long
L
Li
From the State Key Laboratory of Pharmaceutical Biotechnology and MOE Key Laboratory of Model Animal for Disease Study, Model Animal Research Center, Nanjing University, Nanjing 210023, China.
Yahong
Y
Huang
the State Key Laboratory of Protein and Plant Gene Research, College of Life Sciences, Peking University, Beijing 100871, China jijg@pku.edu.cn.
Jianguo
J
Ji
From the State Key Laboratory of Pharmaceutical Biotechnology and MOE Key Laboratory of Model Animal for Disease Study, Model Animal Research Center, Nanjing University, Nanjing 210023, China, ppshen1812@gmail.com.
Pingping
P
Shen
D000818:Animals; D053178:Caspase 6 / Q000276:immunology*; D005260:Female; D015971:Gene Expression Regulation, Enzymologic / Q000276:immunology*; D006801:Humans; D015847:Interleukin-4 / Q000276:immunology; D008262:Macrophage Activation; D017737:Macrophages, Peritoneal / Q000276:immunology* / Q000473:pathology; D015674:Mammary Neoplasms, Animal / Q000276:immunology / Q000473:pathology; D020778:Matrix Metalloproteinase 2 / Q000276:immunology; D020780:Matrix Metalloproteinase 9 / Q000276:immunology; D051379:Mice; D000067996:RAW 264.7 Cells
D015847:Interleukin-4; C505516:Casp6 protein, mouse; D053178:Caspase 6; D020778:Matrix Metalloproteinase 2; C522362:Mmp2 protein, mouse; D020780:Matrix Metalloproteinase 9; C501830:Mmp9 protein, mouse
cell signaling; cytokine; immunology; macrophage; toll-like receptor (TLR); tumor immunology