Abstract
Uncontrolled inflammation leads to tissue damage and it is central for the development of chronic inflammatory diseases and autoimmunity. An acute inflammatory response is finely regulated by the action of anti-inflammatory and pro-resolutive mediators, culminating in the resolution of inflammation and restoration of homeostasis. There are few studies investigating intracellular signaling pathways associated with the resolution of inflammation. Here, we investigate the role of Rho-associated kinase (ROCK), a serine/threonine kinase, in a model of self-resolving neutrophilic inflammatory. We show that ROCK activity, evaluated by P-MYPT-1 kinetics, was higher during the peak of lipopolysaccharide-induced neutrophil influx in the pleural cavity of mice. ROCK inhibition by treatment with Y-27632 decreased the accumulation of neutrophils in the pleural cavity and was associated with an increase in apoptotic events and efferocytosis, as evaluated by an in vivo assay. In a model of gout, treatment with Y-27632 reduced neutrophil accumulation, IL-1β levels and hypernociception in the joint. These were associated with reduced MYPT and IκBα phosphorylation levels and increased apoptosis. Finally, inhibition of ROCK activity also induced apoptosis in human neutrophils and destabilized cytoskeleton, extending the observed effects to human cells. Taken together, these data show that inhibition of the ROCK pathway might represent a potential therapeutic target for neutrophilic inflammatory diseases.
Highlights
A precise control of leukocyte accumulation in inflammatory sites is needed to avoid tissue damage and functional loss of inflamed tissue or organ [1,2,3]
Rho-associated kinase (ROCK) Activity Is Associated with the Productive Phase of Lipopolysaccharide (LPS)-Induced Pleurisy and
We investigated whether ROCK activity was associated with neutrophil accumulation
Summary
A precise control of leukocyte accumulation in inflammatory sites is needed to avoid tissue damage and functional loss of inflamed tissue or organ [1,2,3]. There is a fine-tuned control of inflammatory response by stimulation of events associated with resolution of inflammation. It is evident that resolution of acute inflammation is an active and programmed process highly dependent on the production of pro-resolutive mediators, apoptosis of leukocyte and macrophage reprogramming [4,5,6,7]. Studies have demonstrated that blockage of pro-survival signaling pathways, during inflammation, might induce apoptosis of leukocytes thereby activating the process of resolution. Cells 2019, 8, 964 and Akt inhibitors enhance apoptosis and promote granulocyte clearance, resulting in the resolution of acute inflammation [8,9,10]. Defective apoptosis and clearance are associated with many inflammatory conditions, leading to chronic inflammatory response and autoimmunity [2,12]. Targeting leukocyte survival might be a useful therapeutic strategy for inflammatory diseases
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