A genetic model of constitutively active integrin CD11b/CD18

Laisel Martinez, Xiaobo Li, Gioser Ramos-Echazabal, Hafeez Faridi, Zachary M. Zigmond, Nieves Santos Falcon, Diana R. Hernandez, Serene A. Shehadeh, Omaida C. Velazquez, Vineet Gupta, Roberto I. Vazquez-Padron

Research output: Contribution to journalArticlepeer-review

Abstract

Pharmacological activation of integrin CD11b/CD18 (aMb2, Mac-1, and CR3) shows anti-inflammatory benefits in a variety of animal models of human disease, and it is a novel therapeutic strategy. Reasoning that genetic models can provide an orthogonal and direct system for the mechanistic study of CD11b agonism, we present in this study, to our knowledge, a novel knock-in model of constitutive active CD11b in mice. We genetically targeted the Itgam gene (which codes for CD11b) to introduce a point mutation that results in the I332G substitution in the protein. The I332G mutation in CD11b promotes an active, higher-affinity conformation of the ligand-binding I/A-domain (CD11b aA-domain). In vitro, this mutation increased adhesion of knock-in neutrophils to fibrinogen and decreased neutrophil chemotaxis to a formyl–Met–Leu–Phe gradient. In vivo, CD11bI332G animals showed a reduction in recruitment of neutrophils and macrophages in a model of sterile peritonitis. This genetic activation of CD11b also protected against development of atherosclerosis in the setting of hyperlipidemia via reduction of macrophage recruitment into atherosclerotic lesions. Thus, our animal model of constitutive genetic activation of CD11b can be a useful tool for the study of integrin activation and its potential contribution to modulating leukocyte recruitment and alleviating different inflammatory diseases.

Original languageEnglish (US)
Pages (from-to)2545-2553
Number of pages9
JournalJournal of Immunology
Volume205
Issue number9
DOIs
StatePublished - Nov 1 2020
Externally publishedYes

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

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