Unique and redundant roles of alpha4 and beta2 integrins in kinetics of recruitment of lymphoid vs myeloid cell subsets to the inflamed peritoneum revealed by studies of genetically deficient mice.
OBJECTIVE
Leukocyte recruitment to inflammatory sites is a prominent feature of acute and chronic inflammation. Instrumental in this process is the coordinated upregulation of leukocyte integrins (among which alpha4beta1 and beta2 integrins are major players) and their cognate receptors in inflamed tissues. To avoid the ambiguity of previous short-term antibody-based studies and to allow for long-term observation, we used genetically deficient mice to compare roles of alpha4 and beta2 integrins in leukocyte trafficking.


METHODS
Aseptic peritonitis was induced in alpha4 or beta2 integrin-deficient (conditional and conventional knockouts, respectively) and control mice, and recruitment of major leukocyte subsets to the inflamed peritoneum was followed for up to 4 days.


RESULTS
Despite normal chemokine levels in the peritoneum and adequate numbers, optimal recruitment of myeloid cells was impaired in both alpha4- and beta2-deficient mice. Furthermore, clearance of recruited neutrophils and macrophages was delayed in these mice. Lymphocyte migration to the peritoneum in the absence of alpha4 integrins was drastically decreased, both at steady state and during inflammation, a finding consistent with impaired lymphocyte in vitro adhesion and signaling. By contrast, in the absence of beta2 integrins, defects in lymphocyte recruitment were only evident when peritonitis was established.


CONCLUSIONS
Our data with concurrent use of genetic models of integrin deficiency reveal nonredundant functions of alpha4 integrins in lymphocyte migration to the peritoneum and further refine specific roles of alpha4 and beta2 integrins concerning trafficking and clearance of other leukocyte subsets at homeostasis and during inflammation.
Ulyanova
Tatiana
T
Department of Medicine/Hematology University of Washington, Seattle, WA 98195, USA. ulyant@u.washington.edu
Priestley
Gregory V
GV
Banerjee
Ena Ray
ER
Papayannopoulou
Thalia
T
D000818:Animals; D018821:CD18 Antigens / Q000235:genetics / Q000502:physiology*; D007249:Inflammation / Q000235:genetics* / Q000503:physiopathology*; D039441:Integrin alpha4 / Q000235:genetics / Q000502:physiology*; D007700:Kinetics; D008214:Lymphocytes / Q000502:physiology*; D051379:Mice; D018345:Mice, Knockout; D022423:Myeloid Cells / Q000502:physiology*
D018821:CD18 Antigens; D039441:Integrin alpha4