Activated β2Integrins Restrict Neutrophil Recruitment during Murine Acute Pseudomonal Pneumonia.
Rapid neutrophil recruitment is critical for the efficient clearance of bacterial pathogens from the lungs. Although β2integrins and their activation are required for neutrophil recruitment from postcapillary venules of the systemic circulation into inflamed tissues, the involvement of integrins in neutrophil recruitment in response to respiratory infection varies among bacterial pathogens. For stimuli eliciting β2integrin-dependent neutrophil influx, including Pseudomonas aeruginosa, it remains unclear whether the activation of β2integrins is an essential step in this process. In the current study, we analyze neutrophil trafficking within the lungs of mice infected with Pseudomonas aeruginosa and evaluate the role of β2integrin activation through genetic deletion of talin-1 or Kindlin-3 or by pharmacological inhibition of high-affinity β2integrins using a small molecule allosteric antagonist. We observe that attenuation of high-affinity β2integrins leads to an enhancement of neutrophil emigration into lung interstitium and airspaces. Neutrophil effector functions, including the production of reactive oxygen species and the phagocytosis of bacteria, are only partially dependent on high-affinity β2integrins. These results reveal a mechanism by which activated β2integrins limit neutrophil entry into the lung tissue and airspaces during acute pseudomonal pneumonia and suggest potential strategies for modulating neutrophil-mediated host defense.
1 Division of Surgical Research, Department of Surgery, and.|2 Graduate Program in Pathobiology and.
Zachary S
ZS
Wilson
1 Division of Surgical Research, Department of Surgery, and.
Lawrence B
LB
Ahn
1 Division of Surgical Research, Department of Surgery, and.
William S
WS
Serratelli
4 Department of Radiation Oncology, Rhode Island Hospital, Providence, Rhode Island.|3 Warren Alpert Medical School, Brown University, Providence, Rhode Island.|5 Department of Physics, University of Rhode Island, Kingston, Rhode Island; and.
Matthew D
MD
Belley
1 Division of Surgical Research, Department of Surgery, and.
Joanne
J
Lomas-Neira
6 Department of Biology and Biochemistry, University of Houston, Houston, Texas.
Mehmet
M
Sen
1 Division of Surgical Research, Department of Surgery, and.|3 Warren Alpert Medical School, Brown University, Providence, Rhode Island.
Craig T
0000-0003-3100-877X
CT
Lefort
D000208:Acute Disease; D000818:Animals; D018821:CD18 Antigens / Q000378:metabolism*; D003598:Cytoskeletal Proteins / Q000172:deficiency / Q000378:metabolism; D008168:Lung / Q000098:blood supply / Q000382:microbiology / Q000473:pathology; D008810:Mice, Inbred C57BL; D020556:Neutrophil Infiltration / Q000187:drug effects; D009504:Neutrophils / Q000187:drug effects / Q000378:metabolism; D010795:Phthalic Acids / Q000494:pharmacology; D011014:Pneumonia / Q000276:immunology* / Q000382:microbiology* / Q000473:pathology; D011552:Pseudomonas Infections / Q000276:immunology* / Q000382:microbiology* / Q000473:pathology; D011550:Pseudomonas aeruginosa / Q000187:drug effects / Q000502:physiology*; D015091:beta-Alanine / Q000031:analogs & derivatives / Q000494:pharmacology
D018821:CD18 Antigens; D003598:Cytoskeletal Proteins; D010795:Phthalic Acids; C546917:XVA 143; C527818:kindlin-3 protein, mouse; D015091:beta-Alanine
Pseudomonas aeruginosa; adhesion; integrin activation; neutrophils; pseudomonal pneumonia