TY - JOUR
T1 - Bronchial Epithelial Tet2 Maintains Epithelial Integrity during Acute Pseudomonas aeruginosa Pneumonia
AU - Qin, Wanhai
AU - Brands, Xanthe
AU - van't Veer, Cornelis
AU - de Vos, Alex F.
AU - Scicluna, Brendon P.
AU - van der Poll, Tom
N1 - Funding Information: We thank O. A. Bernard for providing us Tet2fl/fl mice and M. S. ten Brink for helping with the animal experiments. W.Q. is supported by the State Scholarship Fund from the Chinese Scholarship Council (CSC). X.B. is supported by a grant from the Netherlands Organization for Health Research and Development (ZonMW no. 50-53000-98-139). We declare that we have no competing interests. Publisher Copyright: © 2020 American Society for Microbiology. All Rights Reserved. Copyright: Copyright 2021 Elsevier B.V., All rights reserved.
PY - 2021/1/1
Y1 - 2021/1/1
N2 - Respiratory epithelial cells are important for pulmonary innate immune responses during Pseudomonas aeruginosa infection. Tet methylcytosine dioxygenase 2 (Tet2) has been implicated in the regulation of host defense by myeloid and lymphoid cells, but whether Tet2 also contributes to epithelial responses during pneumonia is unknown. The aim of this study was to investigate the role of bronchial epithelial Tet2 in acute pneumonia caused by P. aeruginosa. To this end, we crossed mice with Tet2 flanked by two Lox-P sites (Tet2fl/fl mice) with mice expressing Cre recombinase under the bronchial epithelial cell-specific Cc10 promoter (Cc10Cre mice) to generate bronchial epithelial cell-specific Tet2-deficient (Tet2fl/fl Cc10Cre) mice. Six hours after infection with P. aeruginosa, Tet2fl/fl Cc10Cre and wild-type mice had similar bacterial loads in bronchoalveolar lavage fluid (BALF). At this time point, Tet2fl/fl Cc10Cre mice displayed reduced mRNA levels of the chemokines Cxcl1, Cxcl2, and Ccl20 in bronchial brushes. However, Cxcl1, Cxcl2, and Ccl20 protein levels and leukocyte recruitment in BALF were not different between groups. Tet2fl/fl Cc10Cre mice had increased protein levels in BALF after infection, indicating a disturbed epithelial barrier function, which was corroborated by reduced mRNA expression of tight junction protein 1 and occludin in bronchial brushes. Differences detected between Tet2fl/fl Cc10Cre and wild-type mice were no longer present at 24 h after infection. These results suggest that bronchial epithelial Tet2 contributes to maintaining epithelial integrity by enhancing intracellular connections between epithelial cells during the early phase of P. aeruginosa pneumonia.
AB - Respiratory epithelial cells are important for pulmonary innate immune responses during Pseudomonas aeruginosa infection. Tet methylcytosine dioxygenase 2 (Tet2) has been implicated in the regulation of host defense by myeloid and lymphoid cells, but whether Tet2 also contributes to epithelial responses during pneumonia is unknown. The aim of this study was to investigate the role of bronchial epithelial Tet2 in acute pneumonia caused by P. aeruginosa. To this end, we crossed mice with Tet2 flanked by two Lox-P sites (Tet2fl/fl mice) with mice expressing Cre recombinase under the bronchial epithelial cell-specific Cc10 promoter (Cc10Cre mice) to generate bronchial epithelial cell-specific Tet2-deficient (Tet2fl/fl Cc10Cre) mice. Six hours after infection with P. aeruginosa, Tet2fl/fl Cc10Cre and wild-type mice had similar bacterial loads in bronchoalveolar lavage fluid (BALF). At this time point, Tet2fl/fl Cc10Cre mice displayed reduced mRNA levels of the chemokines Cxcl1, Cxcl2, and Ccl20 in bronchial brushes. However, Cxcl1, Cxcl2, and Ccl20 protein levels and leukocyte recruitment in BALF were not different between groups. Tet2fl/fl Cc10Cre mice had increased protein levels in BALF after infection, indicating a disturbed epithelial barrier function, which was corroborated by reduced mRNA expression of tight junction protein 1 and occludin in bronchial brushes. Differences detected between Tet2fl/fl Cc10Cre and wild-type mice were no longer present at 24 h after infection. These results suggest that bronchial epithelial Tet2 contributes to maintaining epithelial integrity by enhancing intracellular connections between epithelial cells during the early phase of P. aeruginosa pneumonia.
KW - Epithelium integrity
KW - P. aeruginosa
KW - Pneumonia
KW - Tet2
UR - http://www.scopus.com/inward/record.url?scp=85098603231&partnerID=8YFLogxK
U2 - https://doi.org/10.1128/IAI.00603-20
DO - https://doi.org/10.1128/IAI.00603-20
M3 - Article
C2 - 33046509
SN - 0019-9567
VL - 89
JO - Infection and Immunity
JF - Infection and Immunity
IS - 1
M1 - e00603-20
ER -