A Novel Genetic Model of Constitutively Active Integrin CD11b/CD18

• Published in: The Journal of immunology (1950) Vol. 205; no. 9; pp. 2545 - 2553
• Main Authors: Martinez, Laisel, Li, Xiaobo, Ramos-Echazabal, Gioser, Faridi, Hafeez, Zigmond, Zachary M., Falcon, Nieves Santos, Hernandez, Diana R., Shehadeh, Serene A., Velazquez, Omaida C., Gupta, Vineet, Vazquez-Padron, Roberto I.
• Format: Journal Article
• Language: English
• Published: 16.09.2020
• ISSN: 0022-1767; 1550-6606
• DOI: 10.4049/jimmunol.1901402

Pharmacological activation of integrin CD11b/CD18 (α M β 2 , Mac-1, 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 here a novel knock-in (KI) 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 αA-domain). In vitro , this mutation increased adhesion of KI neutrophils to fibrinogen, and decreased neutrophil chemotaxis to a formyl-Met-Leu-Phe (fMLF) gradient. In vivo , CD11b I332G 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.