RhoA determines disease progression by controlling neutrophil motility and restricting hyperresponsiveness.
Neutrophil responses are central to host protection and inflammation. Neutrophil activation follows a 2-step process in which 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. 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.
Conway Institute, School of Medicine and Medical Science, University College Dublin, Dublin, United Kingdom;
Richard T
RT
Jennings
Conway Institute, School of Medicine and Medical Science, University College Dublin, Dublin, United Kingdom;
Monika
M
Strengert
Conway Institute, School of Medicine and Medical Science, University College Dublin, Dublin, United Kingdom;
Patti
P
Hayes
INSERM U773, Université Paris 7 Denis Diderot, Sorbonne Paris Cité, Laboratoire d'Excellence Inflamex, Paris, France; and.
Jamel
J
El-Benna
Biomedical Institute, Biotech Research and Innovation Centre, University of Copenhagen, Copenhagen, Denmark.
Cord
C
Brakebusch
Conway Institute, School of Medicine and Medical Science, University College Dublin, Dublin, United Kingdom;
Malgorzata
M
Kubica
Conway Institute, School of Medicine and Medical Science, University College Dublin, Dublin, United Kingdom;
Ulla G
UG
Knaus
D055371:Acute Lung Injury / Q000235:genetics / Q000276:immunology; D000818:Animals; D002478:Cells, Cultured; D018450:Disease Progression; D005260:Female; D006801:Humans; D007154:Immune System Diseases; D009980:Influenza A virus / Q000276:immunology; D007251:Influenza, Human / Q000276:immunology*; D007960:Leukocyte Disorders; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D009504:Neutrophils / Q000276:immunology*; D009976:Orthomyxoviridae Infections / Q000235:genetics / Q000276:immunology; D011024:Pneumonia, Viral / Q000235:genetics / Q000276:immunology; D020741:rho GTP-Binding Proteins / Q000502:physiology*; D020742:rhoA GTP-Binding Protein
C526380:RhoA protein, mouse; D020741:rho GTP-Binding Proteins; D020742:rhoA GTP-Binding Protein