Role of Myeloid Tet Methylcytosine Dioxygenase 2 in Pulmonary and Peritoneal Inflammation Induced by Lipopolysaccharide and Peritonitis Induced by <i>Escherichia coli</i>
Wanhai Qin,
Xanthe Brands,
Hisatake Matsumoto,
Joe M. Butler,
Cornelis van’t Veer,
Alex F. de Vos,
Joris J. T. H. Roelofs,
Brendon P. Scicluna,
Tom van der Poll
Affiliations
Wanhai Qin
Center of Experimental & Molecular Medicine, Amsterdam University Medical Centers, Location Academic Medical Center, University of Amsterdam, 1105 AZ Amsterdam, The Netherlands
Xanthe Brands
Center of Experimental & Molecular Medicine, Amsterdam University Medical Centers, Location Academic Medical Center, University of Amsterdam, 1105 AZ Amsterdam, The Netherlands
Hisatake Matsumoto
Center of Experimental & Molecular Medicine, Amsterdam University Medical Centers, Location Academic Medical Center, University of Amsterdam, 1105 AZ Amsterdam, The Netherlands
Joe M. Butler
Center of Experimental & Molecular Medicine, Amsterdam University Medical Centers, Location Academic Medical Center, University of Amsterdam, 1105 AZ Amsterdam, The Netherlands
Cornelis van’t Veer
Center of Experimental & Molecular Medicine, Amsterdam University Medical Centers, Location Academic Medical Center, University of Amsterdam, 1105 AZ Amsterdam, The Netherlands
Alex F. de Vos
Center of Experimental & Molecular Medicine, Amsterdam University Medical Centers, Location Academic Medical Center, University of Amsterdam, 1105 AZ Amsterdam, The Netherlands
Joris J. T. H. Roelofs
Department of Pathology, Amsterdam University Medical Centers, Location Academic Medical Center, University of Amsterdam, 1105 AZ Amsterdam, The Netherlands
Brendon P. Scicluna
Center of Experimental & Molecular Medicine, Amsterdam University Medical Centers, Location Academic Medical Center, University of Amsterdam, 1105 AZ Amsterdam, The Netherlands
Tom van der Poll
Center of Experimental & Molecular Medicine, Amsterdam University Medical Centers, Location Academic Medical Center, University of Amsterdam, 1105 AZ Amsterdam, The Netherlands
Tet methylcytosine dioxygenase 2 (Tet2) mediates demethylation of DNA. We here sought to determine the expression and function of Tet2 in macrophages upon exposure to lipopolysaccharide (LPS), and in the host response to LPS induced lung and peritoneal inflammation, and during Escherichia (E.) coli induced peritonitis. LPS induced Tet2 expression in mouse macrophages and human monocytes in vitro, as well as in human alveolar macrophages after bronchial instillation in vivo. Bone marrow-derived macrophages from myeloid Tet2 deficient (Tet2fl/flLysMCre) mice displayed enhanced production of IL-1β, IL-6 and CXCL1 upon stimulation with several Toll-like receptor agonists; similar results were obtained with LPS stimulated alveolar and peritoneal macrophages. Histone deacetylation was involved in the effect of Tet2 on IL-6 production, whilst methylation at the Il6 promoter was not altered by Tet2 deficiency. Tet2fl/flLysMCre mice showed higher IL-6 and TNF levels in bronchoalveolar and peritoneal lavage fluid after intranasal and intraperitoneal LPS administration, respectively, whilst other inflammatory responses were unaltered. E. coli induced stronger production of IL-1β and IL-6 by Tet2 deficient peritoneal macrophages but not in peritoneal lavage fluid of Tet2fl/flLysMCre mice after in vivo intraperitoneal infection. Tet2fl/flLysMCre mice displayed enhanced bacterial growth during E. coli peritonitis, which was associated with a reduced capacity of Tet2fl/flLysMCre peritoneal macrophages to inhibit the growth of E. coli in vitro. Collectively, these data suggest that Tet2 is involved in the regulation of macrophage functions triggered by LPS and during E. coli infection.
