Abstract

Beta2-integrins are complex leukocyte-specific adhesion molecules that are essential for leukocyte (e.g., neutrophil, lymphocyte) trafficking, as well as for other immunological processes such as neutrophil phagocytosis and ROS production, and T cell activation. Intriguingly, however, they have also been found to negatively regulate cytokine responses, maturation, and migratory responses in myeloid cells such as macrophages and dendritic cells, revealing new, and unexpected roles of these molecules in immunity. Because of their essential role in leukocyte function, a lack of expression or function of beta2-integrins causes rare immunodeficiency syndromes, Leukocyte adhesion deficiency type I, and type III (LAD-I and LAD-III). LAD-I is caused by reduced or lost expression of beta2-integrins, whilst in LAD-III, beta2-integrins are expressed but dysfunctional because a major integrin cytoplasmic regulator, kindlin-3, is mutated. Interestingly, some LAD-related phenotypes such as periodontitis have recently been shown to be due to an uncontrolled inflammatory response rather than to an uncontrolled infection, as was previously thought. This review will focus on the recent advances concerning the regulation and functions of beta2-integrins in leukocyte trafficking, immune suppression, and immune deficiency disease.

Highlights

  • Specialty section: This article was submitted to Inflammation, a section of the journal Frontiers in Immunology

  • Beta2-integrins are complex leukocyte-specific adhesion molecules that are essential for leukocyte trafficking, as well as for other immunological processes such as neutrophil phagocytosis and ROS production, and T cell activation

  • Recent studies utilizing T cell-specific filamin A-deficient mice have shown that filamin A is required for the optimal firm adhesion of T cells under shear flow conditions, trafficking of T cells into lymph nodes, and to the inflamed skin [46]. These results demonstrate that in T cells, filamin A does not function as an integrin inhibitor but rather is required for cell trafficking in vivo

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Summary

INTEGRINS AND INTEGRIN REGULATION

Integrins are heterodimeric type I transmembrane proteins consisting of alpha and beta subunits [1]. Beta2-integrins restrict DC migration through a downstream mechanism which involves regulation of the transcriptional program and migratory phenotype of these cells (Figure 1) In addition to their fundamentally important role in leukocyte trafficking, beta2-integrins mediate other cell-cell contacts that are essential for immunological processes (Figure 1). Beta2-integrins has been shown to be required for recruitment of monocytes, as well as hematopoiesis of these cells during Schistosome infection, and a low expression of beta2-integrins correlates with increased parasite burden in a murine model of the disease [78] In addition to their well-characterized role in mediating cellular interactions and promoting pro-inflammatory signaling, beta2-integrins have been associated with many immunosuppressive functions [20] (Figure 1). Manipulating integrin activation pharmacologically could be an efficient therapeutic approach in treating certain inflammatory or autoimmune diseases

LEUKOCYTE ADHESION DEFICIENCIES
LAD III
LAD AND INFLAMMATION
Findings
CONCLUSIONS AND FUTURE PERSPECTIVES

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