A pathway regulating neutrophil integrin inactivation and its contribution to inflammation

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The body's immune cells generate inflammation as part of their defence against infections. But sometimes, immune cells generate inflammation even in the absence of infection. Chronic inflammatory conditions, such as rheumatoid arthritis or multiple sclerosis cause much suffering and pose a massive drain on health services world-wide. To generate inflammation, a type of white blood cell called the neutrophil is essential. Neutrophils are the most common type of white blood cell. Neutrophils are recruited from the blood stream to sites of infection or injury. In order to leave the bloodstream, neutrophils become sticky: they adhere to the inside of the wall of the blood vessel before they transmigrate. This process relies on particular cell surface molecules, the integrins. Integrins exist in a "sticky" (active) and a "non-sticky" (inactive) conformation. It's already known that absence of integrins, or their inability to become activated interferes with the recruitment of neutrophils to sites of infection. A small number of studies analysed integrins that were experimentally rendered permanently active. These activated integrins, too, did not support neutrophil recruitment. We recently showed that a cellular regulator called ARAP3 is important for the regulation of neutrophil integrins, allowing activated integrins to become inactive. Loss of ARAP3 changes the activity profile of the neutrophil. For example, it interferes with migration in the test tube, as neutrophils adhere too firmly to the underlying support. We think that neutrophils need to be able to activate, and inactivate their integrins, "fine-tuning" integrin activity for optimal migration through the body's tissues. Therefore, loss of ARAP3 may also interfere with neutrophil recruitment, and ultimately inflammation. We will study this in the test tube and in models for neutrophil recruitment and for inflammation. We think that ARAP3 is a good target for combating inflammation. This work will build the foundations for new therapeutic approaches targeting chronic inflammation.