Blocking the α4 integrin–paxillin interaction selectively impairs mononuclear leukocyte recruitment to an inflammatory site
Chloé C. Féral, David M. Rose, Jaewon Han, Norma Fox, Gregg J. Silverman, Kenneth Kaushansky, Mark H. Ginsberg
Chloé C. Féral, David M. Rose, Jaewon Han, Norma Fox, Gregg J. Silverman, Kenneth Kaushansky, Mark H. Ginsberg
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Research Article Immunology

Blocking the α4 integrin–paxillin interaction selectively impairs mononuclear leukocyte recruitment to an inflammatory site

Abstract

Antagonists to α4 integrin show promise for several autoimmune and inflammatory diseases but may exhibit mechanism-based toxicities. We tested the capacity of blockade of α4 integrin signaling to perturb functions involved in inflammation, while limiting potential adverse effects. We generated and characterized mice bearing a Y991A mutation in α4 integrin [α4(Y991A) mice], which blocks paxillin binding and inhibits α4 integrin signals that support leukocyte migration. In contrast to the embryonic-lethal phenotype of α4 integrin–null mice, mice bearing the α4(Y991A) mutation were viable and fertile; however, they exhibited defective recruitment of mononuclear leukocytes into thioglycollate-induced peritonitis. α4 Integrins are essential for definitive hematopoiesis; however, the α4(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 α4 integrin signaling can selectively impair mononuclear leukocyte recruitment to sites of inflammation while sparing vital functions of α4 integrins in development and hematopoiesis.

Authors

Chloé C. Féral, David M. Rose, Jaewon Han, Norma Fox, Gregg J. Silverman, Kenneth Kaushansky, Mark H. Ginsberg

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Figure 4

Hematopoiesis in WT and α4(Y991A) mice.

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Disruption of the α4 integrin–paxillin interaction does not interfere wi...
(A) Peripheral blood monocyte counts are shown, the only blood cell type that displayed a statistically significant difference between the 2 strains of mice. *P = 0.041, 2-tailed Student’s t test. (B) The number of BFU-E–, GM-CFU–, and CFU-Mk–derived colonies from WT and α4(Y991A) mice is shown as the mean ± SEM of colonies of each type obtained from 1 × 105 marrow cells from each of 4 mice. A representative example of 3 separate experiments giving essentially identical results is shown. The mean number of colony-forming cells was not statistically different (Student’s t test). (C) The number of GM-CFU derived from the marrow or spleens of lethally irradiated recipient mice following intraocular injection of 2 × 107 marrow cells is shown; the data shown represent the mean ± SEM of results from 4 mice in each group. The number of progenitors that lodged in the marrow (per 1 × 105 cells plated) and spleens (per 2 × 105 cells plated) was not significantly different (2-tailed Student’s t test).