Arhgef1 regulates alpha5beta1 integrin-mediated matrix metalloproteinase expression and is required for homeostatic lung immunity.
Pulmonary immunity depends on the ability of leukocytes to neutralize potentially harmful and frequent insults to the lung, and appropriate regulation of leukocyte migration and adhesion is integral to this process. Arhgef1 is a hematopoietic-restricted signaling molecule that regulates leukocyte migration and integrin-mediated adhesion. To explore a possible regulatory role for Arhgef1 in pulmonary immunity we examined the lung and its leukocytes in wild-type and Arhgef1-deficient animals. Here we report that the lungs of Arhgef1-/- mice harbored significantly more leukocytes, increased expression and activity of matrix metalloproteinases (MMPs), airspace enlargement, and decreased lung elastance compared with wild-type lungs. Transfer of Arhgef1-/- lung leukocytes to wild-type mice led to airspace enlargement and impaired lung function, indicating that loss of Arhgef1 in leukocytes was sufficient to induce pulmonary pathology. Furthermore, we showed that Arhgef1-deficient peritoneal macrophages when either injected into the lungs of wild-type mice or cultured on fibronectin significantly increased expression and activity of MMPs relative to control macrophages, and the in vitro fibronectin induction was dependent on the alpha5beta1 integrin pair. Together these data demonstrate that Arhgef1 regulates alpha5beta1-mediated MMP expression by macrophages and that loss of Arhgef1 by leukocytes leads to pulmonary pathology.
Hartney
John M
JM
Integrated Department of Immunology, University of Colorado Denver and National Jewish Health, 1400 Jackson St., Denver, CO 80206, USA.
Brown
Jeanette
J
Chu
Hong Wei
HW
Chang
Ling Yi
LY
Pelanda
Roberta
R
Torres
Raul M
RM
D000818:Animals; D001696:Biomechanical Phenomena / Q000187:drug effects; D001992:Bronchoalveolar Lavage Fluid / Q000166:cytology; D002478:Cells, Cultured; D005353:Fibronectins / Q000494:pharmacology; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D020662:Guanine Nucleotide Exchange Factors / Q000172:deficiency / Q000378:metabolism*; D006706:Homeostasis / Q000187:drug effects / Q000276:immunology*; D007109:Immunity / Q000187:drug effects / Q000276:immunology*; D039081:Integrin alpha5beta1 / Q000378:metabolism*; D007958:Leukocyte Count; D007962:Leukocytes / Q000187:drug effects / Q000201:enzymology / Q000473:pathology; D008024:Ligands; D008168:Lung / Q000201:enzymology* / Q000276:immunology* / Q000473:pathology / Q000503:physiopathology; D017737:Macrophages, Peritoneal / Q000187:drug effects / Q000201:enzymology / Q000473:pathology; D020782:Matrix Metalloproteinases / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D011518:Proto-Oncogene Proteins / Q000172:deficiency / Q000378:metabolism*; D012129:Respiratory Function Tests; D064067:Rho Guanine Nucleotide Exchange Factors; D015398:Signal Transduction / Q000187:drug effects
C577231:Arhgef1 protein, mouse; D005353:Fibronectins; D020662:Guanine Nucleotide Exchange Factors; D039081:Integrin alpha5beta1; D008024:Ligands; D011518:Proto-Oncogene Proteins; D064067:Rho Guanine Nucleotide Exchange Factors; D020782:Matrix Metalloproteinases