ROCK Inhibition Drives Resolution of Acute Inflammation by Enhancing Neutrophil Apoptosis

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.

Susceptibility Factors in Chronic Lung Inflammatory Responses to Engineered Nanomaterials

“…Inflammation is the consequence of an innate immune response of the host to stimuli such as pathogens (e.g., bacteria, fungi, viruses), allergens, or toxic chemicals and pollutants [ 1 , 2 , 3 ]. The steps in the inflammatory response can be defined as (1) induction, (2) peak, and (3) resolution [ 1 , 2 , 4 , 5 , 6 , 7 ]. The induction phase involves innate immune cells (e.g., macrophages) detecting the pathogen or other foreign agent and orchestrating the recruitment of other innate immune cells (e.g., neutrophils, eosinophils) to the site of infection and/or injury [ 1 , 2 , 5 , 6 , 7 ].…”

“…The steps in the inflammatory response can be defined as (1) induction, (2) peak, and (3) resolution [ 1 , 2 , 4 , 5 , 6 , 7 ]. The induction phase involves innate immune cells (e.g., macrophages) detecting the pathogen or other foreign agent and orchestrating the recruitment of other innate immune cells (e.g., neutrophils, eosinophils) to the site of infection and/or injury [ 1 , 2 , 5 , 6 , 7 ]. The peak of inflammation involves recruited innate immune cells (e.g., macrophages, monocytes, neutrophils) engulfing pathogens or inhaled agents, triggering key defensive mechanisms, notably the generation of reactive oxygen species (i.e., respiratory burst) from macrophages and the release of neutrophil extracellular traps (NETs) from recruited neutrophils [ 1 , 2 , 3 , 4 , 5 , 6 , 7 ].…”

“…The induction phase involves innate immune cells (e.g., macrophages) detecting the pathogen or other foreign agent and orchestrating the recruitment of other innate immune cells (e.g., neutrophils, eosinophils) to the site of infection and/or injury [ 1 , 2 , 5 , 6 , 7 ]. The peak of inflammation involves recruited innate immune cells (e.g., macrophages, monocytes, neutrophils) engulfing pathogens or inhaled agents, triggering key defensive mechanisms, notably the generation of reactive oxygen species (i.e., respiratory burst) from macrophages and the release of neutrophil extracellular traps (NETs) from recruited neutrophils [ 1 , 2 , 3 , 4 , 5 , 6 , 7 ]. Recruited innate immune cells also secrete a plethora of cytokines (e.g., IL-6, IL-1β, TNF-α) and chemokines (e.g., CXC and CC motif chemokines) that have numerous functions (e.g., cell proliferation, cell migration, cell death, alteration of epithelial or endothelial barrier permeability) and also serve as extracellular signals that bridge the innate and adaptive immune systems.…”

“…The resolution of inflammation involves clearance of foreign agents, removal of recruited host immune cells, and repair of damaged tissue [ 8 , 9 ]. During an acute inflammatory response, the body’s innate immune system defends against the foreign agent in order to remove the invading threat and to heal the damaged tissue through the recruitment of various immune cells such as neutrophils, monocytes, macrophages, lymphocytes, and plasma cells [ 1 , 2 , 3 , 4 , 5 , 6 , 7 , 8 , 9 ]. The induction of acute inflammation is a rapid process that occurs within hours and resolves within days, where the immune process is more localized to the specific injury site [ 9 , 10 ].…”

“…The induction of acute inflammation is a rapid process that occurs within hours and resolves within days, where the immune process is more localized to the specific injury site [ 9 , 10 ]. This acute inflammatory response is critical to restore the body back to a state of homeostasis after injury [ 5 , 6 , 7 , 8 , 9 , 10 ]. However, when acute inflammation fails to resolve or multiple exposures dysregulate the immune system, this may lead to unresolved chronic inflammation [ 4 , 5 , 6 , 7 , 8 , 9 , 10 ].…”