Impaired intracellular signaling, myeloperoxidase release and bactericidal activity of neutrophils from patients with alcoholic cirrhosis

NADPH oxidase depletion in neutrophils from patients with cirrhosis and restoration via toll-like receptor 7/8 activation

“…Our data provide first evidence that neutrophils from patients with advanced alcoholic cirrhosis exhibit a severe deficient expression of the flavocytochrome b558 (gp91 phox /NOX2 and p22 phox ), p47 phox but not p67 phox , thus providing explanations to their impaired ROS production induced by various stimuli21 26 and deficient bactericidal activity 27. Impairment of gp91 phox involved two processes; a proteolytic degradation via elastase present in patients’ plasma or released during neutrophil exocytosis, and a defective gp91 phox translational machinery, both leading to gp91 phox depletion.…”

“…Among five candidates detected (see online supplementary table 1), elastase was the unique protease from neutrophils. To examine its potential contribution to gp91 phox degradation, a first approach was used by treating healthy neutrophils with purified elastase at 0.1 and 0.5U, which provided a proteolytic activity similar to that obtained with supernatants from degranulating neutrophils 27. This treatment also led to gp91 phox cleavage, as shown by the concomitant increase of immune-reactive gp91 phox fragments (figure 3A) and the dramatic decreased surface expression of gp91 phox (see online supplementary figure 2).…”

“…MAP kinases are also important signalling effectors of receptors of the innate immunity such as TLR 33. We previously showed that activation of intracellular TRL7/8 by CL097 greatly potentiated AKT and MAP kinase signalling and reversed the deficient degranulation and bactericidal activity of patients’ neutrophils 27. Based on these observations, we examined whether NOX2 expression/activity was improved.…”

“…However, during disease progression to cirrhosis, neutrophils become altered with impairment of ROS production, phagocytosis and exocytosis,14 19–27 which promotes microbial infection. Although the biochemical mechanisms underlying these functional defects remain largely unknown, an impaired signalling was observed affecting phospholipase C,21mitogen-activated protein kinases (MAPK),26 27 AKT27 and a novel signalling axis, mTOR/p38-MAPK/p47 phox(ref26) associated with a severe impaired ROS production in neutrophils from patients with alcoholic cirrhosis 26. Whether impairment of neutrophil oxygen-dependent antimicrobial function is related to altered expression of NADPH oxidase remains unexplored.…”

Targeting toll-like receptor 7/8 improves host anti-infective response in alcoholic cirrhosis

“…A deficit of gp91 phox also accounts for the lowering in ROS-mediated bacterial killing by monocytes of patients with alcoholic hepatitis,8 indicating that in alcohol abusers, similar mechanisms can be responsible for affecting the functions of different phagocytic cells. Interestingly, TLR-7/8 stimulation of AKT/mTOR also contributes to restore neutrophil’s bactericidal activity by promoting myeloperoxidase release9 (figure 1). Nonetheless, several issues remain still open.…”