1 Section of Molecular Pathology, Department of Biomedical Sciences, Faculty of Health and Medical Sciences, Københavns Universitet2 Department of Biomedical Sciences, Department of Biomedical Sciences, Faculty of Health and Medical Sciences, Københavns Universitet3 Conway Institute, School of Medicine and Medical Science, University College Dublin, Dublin, Ireland;4 unknown5 Brakebusch Group, BRIC, Faculty of Health and Medical Sciences, Københavns Universitet6 Brakebusch Group, BRIC, Faculty of Health and Medical Sciences, Københavns Universitet
Neutrophil responses are central to host protection and inflammation. Neutrophil activation follows a two-step process where priming amplifies responses to activating stimuli. Priming is essential for life span extension, chemotaxis and respiratory burst activity. Here we show that the cytoskeletal organizer RhoA suppresses neutrophil 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. While even restricted influx of Rho-deficient hyperactive neutrophils exacerbated LPS-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.