title: Ecto-5'-nucleotidase CD73 modulates the innate immune response to influenza infection but is not required for development of influenza-induced acute lung injury.
abstract: Extracellular nucleotides and nucleosides are important signaling molecules in the lung. Nucleotide and nucleoside concentrations in alveolar lining fluid are controlled by a complex network of surface ectonucleotidases. Previously, we demonstrated that influenza A/WSN/33 (H1N1) virus resulted in increased levels of the nucleotide ATP and the nucleoside adenosine in bronchoalveolar lavage fluid (BALF) of wild-type (WT) C57BL/6 mice. Influenza-induced acute lung injury (ALI) was highly attenuated in A1-adenosine receptor-knockout mice. Because AMP hydrolysis by the ecto-5'-nucleotidase (CD73) plays a central role in and is rate-limiting for generation of adenosine in the normal lung, we hypothesized that ALI would be attenuated in C57BL/6-congenic CD73-knockout (CD73-KO) mice. Infection-induced hypoxemia, bradycardia, viral replication, and bronchoconstriction were moderately increased in CD73-KO mice relative to WT controls. However, postinfection weight loss, pulmonary edema, and parenchymal dysfunction were not altered. Treatment of WT mice with the CD73 inhibitor 5'-(α,β-methylene) diphosphate (APCP) also had no effect on infection-induced pulmonary edema but modestly attenuated hypoxemia. BALF from CD73-KO and APCP-treated WT mice contained more IL-6 and CXCL-10/IFN-γ-induced protein 10, less CXCL-1/keratinocyte chemoattractant, and fewer neutrophils than BALF from untreated WT controls. BALF from APCP-treated WT mice also contained fewer alveolar macrophages and more transforming growth factor-β than BALF from untreated WT mice. These results indicate that CD73 is not necessary for development of ALI following influenza A virus infection and suggest that tissue-nonspecific alkaline phosphatase may be responsible for increased adenosine generation in the infected lung. However, they do suggest that CD73 has a previously unrecognized immunomodulatory role in influenza.
authors.affiliation: Department of Veterinary Biosciences, The Ohio State University, Columbus, Ohio.
authors.forename: Famke
authors.initials: F
authors.lastname: Aeffner
authors.affiliation: Department of Veterinary Biosciences, The Ohio State University, Columbus, Ohio.
authors.forename: Parker S
authors.initials: PS
authors.lastname: Woods
authors.affiliation: Department of Veterinary Biosciences, The Ohio State University, Columbus, Ohio davis.2448@osu.edu.
authors.forename: Ian C
authors.initials: IC
authors.lastname: Davis
mesh_terms: D015720:5'-Nucleotidase / Q000235:genetics / Q000378:metabolism*; D055371:Acute Lung Injury / Q000150:complications / Q000201:enzymology* / Q000276:immunology* / Q000821:virology; D000255:Adenosine Triphosphate / Q000031:analogs & derivatives / Q000494:pharmacology; D000469:Alkaline Phosphatase / Q000378:metabolism; D000818:Animals; D001992:Bronchoalveolar Lavage Fluid / Q000166:cytology; D018925:Chemokines / Q000378:metabolism; D003187:Compliance; D058851:GPI-Linked Proteins / Q000235:genetics / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects; D006321:Heart / Q000187:drug effects / Q000503:physiopathology; D006801:Humans; D007113:Immunity, Innate / Q000187:drug effects; D053118:Influenza A Virus, H1N1 Subtype / Q000276:immunology; D007251:Influenza, Human / Q000276:immunology*; D007958:Leukocyte Count; D008168:Lung / Q000187:drug effects / Q000503:physiopathology; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009504:Neutrophils / Q000166:cytology / Q000187:drug effects; D009976:Orthomyxoviridae Infections / Q000150:complications / Q000201:enzymology* / Q000276:immunology* / Q000821:virology; D011654:Pulmonary Edema / Q000209:etiology / Q000473:pathology / Q000503:physiopathology; D014779:Virus Replication / Q000187:drug effects
chemical_list: D018925:Chemokines; D058851:GPI-Linked Proteins; C005147:5'-adenylyl (beta,gamma-methylene)diphosphonate; D000255:Adenosine Triphosphate; C510878:ALPL protein, mouse; D000469:Alkaline Phosphatase; D015720:5'-Nucleotidase; C548242:Nt5e protein, mouse
keywords: CD73; acute lung injury; adenosine; influenza; mouse