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 2

The recruitment of mononuclear leukocytes to the peritoneum in response to thioglycollate is impaired in mice with disrupted α4 integrin-paxillin interaction.

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The recruitment of mononuclear leukocytes to the peritoneum in response ...
(A–C) WT and α4(Y991A) mice were injected intraperitoneally with thioglycollate, and peritoneal lavage fluid collected at the indicated time points. Total cell number in the lavage fluid was measured with a hemocytometer, and differential cell counts were performed on cytospin slides after modified Wright-Giemsa staining. Results are shown for total lymphocyte (A), monocyte/macrophage (B), and neutrophil (C) counts. *P = 0.013, 2-tailed Student’s t test. Results are mean ± SEM of 4–8 mice for each time point. (D) Ratios of adoptively transferred WT/α4(Y991A) splenic lymphocytes found in the spleen, blood, peripheral LN (PLN), mesenteric LN (MLN), and thioglycollate-induced inflamed peritoneal cavities (Periton.) of recipient WT mice. Ratios of differentially labeled cells were assessed by flow cytometry and normalized to the starting input ratio. Results are mean ± SEM of 8 mice from 3 separate experiments. **P = 0.037, WT vs. α4(Y991A), 1-tailed Student’s t test.