Distinct Effects of Integrins α X β 2 and α M β 2 on Leukocyte Subpopulations during Inflammation and Antimicrobial Responses

Abstract

ABSTRACT Integrins α M β 2 and α X β 2 are homologous adhesive receptors that are expressed on many of the same leukocyte populations and bind many of the same ligands. Although α M β 2 was extensively characterized and implicated in leukocyte inflammatory and immune functions, the roles of α X β 2 remain largely obscure. Here, we tested the ability of mice deficient in integrin α M β 2 or α X β 2 to deal with opportunistic infections and the capacity of cells derived from these animals to execute inflammatory functions. The absence of α M β 2 affected the recruitment of polymorphonuclear neutrophils (PMN) to bacterial and fungal pathogens as well as to model inflammatory stimuli, and α M β 2 -deficient PMN displayed defective inflammatory functions. In contrast, deficiency of α X β 2 abrogated intraperitoneal recruitment and adhesive functions of monocytes and macrophages (Mϕ) and the ability of these cells to kill/phagocytose Candida albicans or Escherichia coli cells both ex vivo and in vivo . During systemic candidiasis, the absence of α X β 2 resulted in the loss of antifungal activity by tissue Mϕ and inhibited the production of tumor necrosis factor alpha (TNF-α)/interleukin-6 (IL-6) in infected kidneys. Deficiency of α M β 2 suppressed Mϕ egress from the peritoneal cavity, decreased the production of anti-inflammatory IL-10, and stimulated the secretion of IL-6. The absence of α X β 2 , but not of α M β 2 , increased survival against a septic challenge with lipopolysaccharide (LPS) by 2-fold. Together, these results suggest that α M β 2 plays a primary role in PMN inflammatory functions and regulates the anti-inflammatory functions of Mϕ, whereas α X β 2 is central in the regulation of inflammatory functions of recruited and tissue-resident Mϕ.