Blocking neutrophil integrin activation prevents ischemia-reperfusion injury.

Abstract

Neutrophil recruitment, mediated by β2 integrins, combats pyogenic infections but also plays a key role in ischemia-reperfusion injury and other inflammatory disorders. Talin induces allosteric rearrangements in integrins that increase affinity for ligands (activation). Talin also links integrins to actin and other proteins that enable formation of adhesions. Structural studies have identified a talin1 mutant (L325R) that perturbs activation without impairing talin's capacity to link integrins to actin and other proteins. Here, we found that mice engineered to express only talin1(L325R) in myeloid cells were protected from renal ischemia-reperfusion injury. Dissection of neutrophil function in vitro and in vivo revealed that talin1(L325R) neutrophils had markedly impaired chemokine-induced, β2 integrin-mediated arrest, spreading, and migration. Surprisingly, talin1(L325R) neutrophils exhibited normal selectin-induced, β2 integrin-mediated slow rolling, in sharp contrast to the defective slow rolling of neutrophils lacking talin1 or expressing a talin1 mutant (W359A) that blocks talin interaction with integrins. These studies reveal the importance of talin-mediated activation of integrins for renal ischemia-reperfusion injury. They further show that neutrophil arrest requires talin recruitment to and activation of integrins. However, although neutrophil slow rolling requires talin recruitment to integrins, talin-mediated integrin activation is dispensable.

• Authors: Tadayuki Yago, Brian G Petrich, Nan Zhang, Zhenghui Liu, Bojing Shao, Mark H Ginsberg, Rodger P McEver
• Journal: The Journal of experimental medicine (J Exp Med) Vol. 212 Issue 8 Pg. 1267-81 (Jul 27 2015) ISSN: 1540-9538 [Electronic] United States
• PMID: 26169939 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)
• Copyright: © 2015 Yago et al.

Chemical References

• CD18 Antigens
• DNA Primers
• Talin
• talin protein, mouse

Topics

• Animals
• Blotting, Western
• CD18 Antigens (metabolism)
• Cell Movement (genetics)
• DNA Primers (genetics)
• Immunoprecipitation
• Kidney Diseases (genetics, prevention & control)
• Leukocyte Rolling (physiology)
• Mice
• Mice, Transgenic
• Mutation, Missense (genetics)
• Neutrophils (metabolism, physiology)
• Reperfusion Injury (genetics, prevention & control)
• Talin (genetics, metabolism)