RhoA GAP Myo9b regulates β2-integrin activity and neutrophil recruitment during murine acute kidney injury Available to Purchase

• RhoA GAP Myo9b controls actin cytoskeleton rearrangement and neutrophil recruitment under inflammatory conditions

• Myo9b regulates RhoA activity, which is essential for chemokine- and selectin-induced Rap1 and talin-1 dependent β2‐integrin activation

An acute inflammatory response to infection or sterile injury involves an adequate activation and recruitment of leukocytes. Activation of β2-integrins is required for neutrophil recruitment and is also mandatory for various neutrophil cell-intrinsic functions. GTPases are key regulators of the actin cytoskeleton and are required for β2‐integrin activation. MyosinIXb (Myo9b), a Rho GTPase-activating protein, is essential for regulating Rho activity in neutrophils. Yet, the exact molecular mechanism how Myo9b regulates β2-integrin activity and neutrophil recruitment into inflamed tissue is unknown. We demonstrate that Myo9b deficiency causes RhoA overactivation, increases actin cytoskeleton rearrangement in neutrophils, decreases neutrophil recruitment into the kidney and improves kidney function in murine models of acute kidney injury. Loss of Myo9b also affects neutrophil effector functions and causes increased rolling velocity, decreased adhesion, impaired crawling, and strongly reduced transmigration of neutrophils in vivo. Mechanistically, Myo9b regulates RhoA activity which is required for chemokine- and selectin-induced talin-1 recruitment to β2‐integrins. Thus, Myo9b is a crucial regulator of important signaling pathways in neutrophils and is required for an adequate immune response triggered by chemokines and selectins.