Blocking the alpha 4 integrin-paxillin interaction selectively impairs mononuclear leukocyte recruitment to an inflammatory site.
Antagonists to alpha4 integrin show promise for several autoimmune and inflammatory diseases but may exhibit mechanism-based toxicities. We tested the capacity of blockade of alpha4 integrin signaling to perturb functions involved in inflammation, while limiting potential adverse effects. We generated and characterized mice bearing a Y991A mutation in alpha4 integrin [alpha4(Y991A) mice], which blocks paxillin binding and inhibits alpha4 integrin signals that support leukocyte migration. In contrast to the embryonic-lethal phenotype of alpha4 integrin-null mice, mice bearing the alpha4(Y991A) mutation were viable and fertile; however, they exhibited defective recruitment of mononuclear leukocytes into thioglycollate-induced peritonitis. Alpha4 integrins are essential for definitive hematopoiesis; however, the alpha4(Y991A) mice had intact lymphohematopoiesis and, with the exception of reduced Peyer's patches, normal architecture and cellularity of secondary lymphoid tissues. We conclude that interference with alpha4 integrin signaling can selectively impair mononuclear leukocyte recruitment to sites of inflammation while sparing vital functions of alpha4 integrins in development and hematopoiesis.
Department of Medicine, University of California San Diego, La Jolla, California 92093-0726, USA.
Chloé C
CC
Féral
David M
DM
Rose
Jaewon
J
Han
Norma
N
Fox
Gregg J
GJ
Silverman
Kenneth
K
Kaushansky
Mark H
MH
Ginsberg
D019943:Amino Acid Substitution / Q000235:genetics; D000818:Animals; D002454:Cell Differentiation / Q000502:physiology; D002465:Cell Movement / Q000235:genetics; D005260:Female; D006410:Hematopoiesis / Q000235:genetics; D018836:Inflammation Mediators / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D039441:Integrin alpha4 / Q000235:genetics* / Q000378:metabolism; D007963:Leukocytes, Mononuclear / Q000378:metabolism / Q000473:pathology*; D051379:Mice; D008817:Mice, Mutant Strains; D051419:Paxillin / Q000037:antagonists & inhibitors* / Q000378:metabolism; D010538:Peritonitis / Q000378:metabolism / Q000473:pathology; D010581:Peyer's Patches / Q000166:cytology / Q000254:growth & development
D018836:Inflammation Mediators; D051419:Paxillin; C496062:Pxn protein, mouse; D039441:Integrin alpha4