RhoA determines disease progression by controlling neutrophil motility and restricting hyperresponsiveness

TY - JOUR

T1 - RhoA determines disease progression by controlling neutrophil motility and restricting hyperresponsiveness

AU - Jennings, Richard T

AU - Strengert, Monika

AU - Hayes, Patti

AU - El-Benna, Jamel

AU - Brakebusch, Cord Herbert

AU - Kubica, Malgorzata

AU - Knaus, Ulla G

PY - 2014/6/5

Y1 - 2014/6/5

N2 - Neutrophil responses are central to host protection and inflammation. Neutrophil activation follows a 2-stepprocess in which priming amplifies responses to activating stimuli. Priming isessential for life span extension, chemotaxis, and respiratory burst activity. Here we show that the cytoskeletal organizer RhoA suppresses neutro phil priming via formins. Premature granule exocytosis in Rho-deficient neutrophils activated numerous signaling pathways and amplified superoxide generation. Deletion of Rho altered front-to-back coordination by simultaneously increasing uropod elongation, leading edge formation, and random migration. Concomitant negative and positive regulation of β2 integrin-independent and β2 integrin-dependent migration, respectively, reveal Rho as a key decision point in the neutrophil response to discrete chemotactic agents. Although even restricted influx of Rho-deficient hyperactive neutrophils exacerbated lipopolysaccharide-mediated lung injury, deleting Rho in innate immune cells was highly protective in influenza A virus infection. Hence, Rho is a key regulator of disease progression by maintaining neutrophil quiescence and suppressing hyperresponsiveness.

AB - Neutrophil responses are central to host protection and inflammation. Neutrophil activation follows a 2-stepprocess in which priming amplifies responses to activating stimuli. Priming isessential for life span extension, chemotaxis, and respiratory burst activity. Here we show that the cytoskeletal organizer RhoA suppresses neutro phil priming via formins. Premature granule exocytosis in Rho-deficient neutrophils activated numerous signaling pathways and amplified superoxide generation. Deletion of Rho altered front-to-back coordination by simultaneously increasing uropod elongation, leading edge formation, and random migration. Concomitant negative and positive regulation of β2 integrin-independent and β2 integrin-dependent migration, respectively, reveal Rho as a key decision point in the neutrophil response to discrete chemotactic agents. Although even restricted influx of Rho-deficient hyperactive neutrophils exacerbated lipopolysaccharide-mediated lung injury, deleting Rho in innate immune cells was highly protective in influenza A virus infection. Hence, Rho is a key regulator of disease progression by maintaining neutrophil quiescence and suppressing hyperresponsiveness.

U2 - 10.1182/blood-2014-02-557843

DO - 10.1182/blood-2014-02-557843

M3 - Journal article

C2 - 24782506

SN - 0006-4971

VL - 123

SP - 3635

EP - 3645

JO - Blood

JF - Blood

IS - 23

ER -