Dendritic cell integrin expression patterns regulate inflammation in the rheumatoid arthritis joint.

OBJECTIVES: Immune dysregulation contributes to the development of RA. Altered surface expression patterns of integrin adhesion receptors by immune cells is one mechanism by which this may occur. We investigated the role of ß2 integrin subunits CD11a and CD11b in dendritic cell (DC) subsets of RA patients. METHODS: Total ß2 integrin subunit expression and its conformation ('active' vs 'inactive' state) were quantified in DC subsets from peripheral blood (PB) and SF of RA patients as well as PB from healthy controls. Ex vivo stimulation of PB DC subsets and in vitro-generated mature and tolerogenic monocyte-derived DCs (moDCs) were utilized to model the clinical findings. Integrin subunit contribution to DC function was tested by analysing clustering and adhesion, and in co-cultures to assess T cell activation. RESULTS: A significant reduction in total and active CD11a expression in DCs in RA SF compared with PB and, conversely, a significant increase in CD11b expression was found. These findings were modelled in vitro using moDCs: tolerogenic moDCs showed higher expression of active CD11a and reduced levels of active CD11b compared with mature moDCs. Finally, blockade of CD11b impaired T cell activation in DC-T cell co-cultures. CONCLUSION: For the first time in RA, we show opposing expression of CD11a and CD11b in DCs in environments of inflammation (CD11alow/CD11bhigh) and steady state/tolerance (CD11ahigh/CD11blow), as well as a T cell stimulatory role for CD11b. These findings highlight DC integrins as potential novel targets for intervention in RA.

ß2 Integrins As Regulators of Dendritic Cell, Monocyte, and Macrophage Function.

Emerging evidence suggests that the ß2 integrin family of adhesion molecules have an important role in suppressing immune activation and inflammation. ß2 integrins are important adhesion and signaling molecules that are exclusively expressed on leukocytes. The four ß2 integrins (CD11a, CD11b, CD11c, and CD11d paired with the ß2 chain CD18) play important roles in regulating three key aspects of immune cell function: recruitment to sites of inflammation; cell-cell contact formation; and downstream effects on cellular signaling. Through these three processes, ß2 integrins both contribute to and regulate immune responses. This review explores the pro- and anti-inflammatory effects of ß2 integrins in monocytes, macrophages, and dendritic cells and how they influence the outcome of immune responses. We furthermore discuss how imbalances in ß2 integrin function can have far-reaching effects on mounting appropriate immune responses, potentially influencing the development and progression of autoimmune and inflammatory diseases. Therapeutic targeting of ß2 integrins, therefore, holds enormous potential in exploring treatment options for a variety of inflammatory conditions.