AUTHOR=Liu Min , Bedouhene Samia , Hurtado-Nedelec Margarita , Pintard Coralie , Dang Pham My-chan , Yu Shiyuan , El-Benna Jamel 

TITLE=The Prolyl Isomerase Pin1 Controls Lipopolysaccharide-Induced Priming of NADPH Oxidase in Human Neutrophils

JOURNAL=Frontiers in Immunology

VOLUME=10

YEAR=2019

URL=https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2019.02567

DOI=10.3389/fimmu.2019.02567

ISSN=1664-3224

ABSTRACT=<p>Production of superoxide anion and other reactive oxygen species (ROS) by neutrophils has a vital role in host defense against microbes. However, over-production can induce cell injury participating to inflammation. Superoxide anion is produced by the phagocyte NADPH oxidase/NOX2, a multicomponent enzyme system consisting of six proteins: two trans-membrane proteins (gp91<sup><italic>phox</italic></sup> and p22<sup><italic>phox</italic></sup>) and four soluble cytosolic proteins (p40<sup><italic>phox</italic></sup>, p67<sup><italic>phox</italic></sup>, p47<sup><italic>phox</italic></sup>, and the small G-proteins, Rac1/2). Phosphorylation of p47<sup><italic>phox</italic></sup> on several serines regulates NADPH oxidase activation. LPS released by gram negative bacteria can enhance or prime neutrophil superoxide production in combination with other agonists such as the bacterial peptide formyl-Met-Leu-Phe (fMLP). Since the pathways involved in LPS-induced priming are not completely understood, we investigated the role of the prolyl <italic>cis/trans</italic> isomerase Pin1 in this process. Two different Pin1 inhibitors, PiB, and Juglone are able to block LPS-induced priming of ROS production by human neutrophils in a concentration dependent manner. PiB and Juglone did not inhibit LPS-induced CD11b translocation neither CD62L shedding. LPS induced an increase of Pin1 activity in neutrophils similar to TNFα and fMLP. Since the phosphorylation of p47<sup><italic>phox</italic></sup> on Ser345 is critical for NADPH oxidase up-regulation, we investigated the effect of LPS on this process. Results show that LPS induced the phosphorylation of p47<sup><italic>phox</italic></sup> mainly on serine 345 and induced the activation of p38MAPKinase and ERK1/2. These results suggest that the prolyl <italic>cis/trans</italic> isomerase Pin1 may control LPS-induced priming of superoxide production in human neutrophils. Pharmacological targeting of Pin1 could be a valuable approach in sepsis.</p>