Impaired inflammasome activation and bacterial clearance in G6PD deficiency due to defective NOX/p38 MAPK/AP-1 redox signaling

Abstract

Glucose-6-phosphate dehydrogenase (G6PD) is the rate-limiting enzyme of the pentose phosphate pathway that modulates cellular redox homeostasis via the regeneration of NADPH. G6PD-deficient cells have a reduced ability to induce the innate immune response, thus increasing host susceptibility to pathogen infections. An important part of the immune response is the activation of the inflammasome. G6PD-deficient peripheral blood mononuclear cells (PBMCs) from patients and human monocytic (THP-1) cells were used as models to investigate whether G6PD modulates inflammasome activation. A decreased expression of IL-1β was observed in both G6PD-deficient PBMCs and PMA-primed G6PD-knockdown (G6PD-kd) THP-1 cells upon lipopolysaccharide (LPS)/adenosine triphosphate (ATP) or LPS/nigericin stimulation. The pro-IL-1β expression of THP-1 cells was decreased by G6PD knockdown at the transcriptional and translational levels in an investigation of the expression of the inflammasome subunits. The phosphorylation of p38 MAPK and downstream c-Fos expression were decreased upon G6PD knockdown, accompanied by decreased AP-1 translocation into the nucleus. Impaired inflammasome activation in G6PD-kd THP-1 cells was mediated by a decrease in the production of reactive oxygen species (ROS) by NOX signaling, while treatment with hydrogen peroxide (H 2 O 2 ) enhanced inflammasome activation in G6PD-kd THP-1 cells. G6PD knockdown decreased Staphylococcus aureus and Escherichia coli clearance in G6PD-kd THP-1 cells and G6PD-deficient PBMCs following inflammasome activation. These findings support the notion that enhanced pathogen susceptibility in G6PD deficiency is, in part, due to an altered redox signaling, which adversely affects inflammasome activation and the bactericidal response.Abbreviations: G6PD, glucose-6-phosphate dehydrogenase; NADPH, reduced form of nicotinamide adenine dinucleotide phosphate; NOX, NADPH oxidase; NO, nitric oxide; NOS, nitric oxide synthase; UP-LPS, ultrapure lipopolysaccharide; PMA, phorbol 12-myristate 13-acetate; ATP, adenosine triphosphate; MAPK, mitogenactivated protein kinases; AP-1, activator protein 1; ROS, reactive oxygen species; PBMC, peripheral blood mononuclear cells; H 2 O 2 , hydrogen peroxide; THP-1, human monocytic cells; G6PD-kd, G6PD knockdown

G6PD deficiency and severity of COVID19 pneumonia and acute respiratory distress syndrome: tip of the iceberg?

“…There is now accumulating evidence that G6PD de ciency affects cells other than erythrocytes 10,[21][22][23][24] . The replication and spread of respiratory viruses normally involves activation of the antiviral innate immune responses and culminates in the production of type I interferons (IFNs) and proin ammatory cytokines such as tumor necrosis factor-alpha (TNF-α), which in turn upregulate antiviral proteins 24 .…”

“…In another study, G6PD-de cient peripheral blood mononuclear cells (PBMCs) from patients and human monocytic (THP-1) cells showed impaired in ammasome activation. In particular, G6PD knockdown reduced the expression of mature interleukin (IL)-1β but not the expression of caspase-1 or the components of the in ammasome (NLRP3, ASC, and pro-Caspase-1) pathway 10 . Additionally, there was a differential expression of cytokines between the G6PD-de cient cells and the normal cells.…”

“…We report here the clinical scenarios of six COVID19-positive patients with no previous respiratory issues with G6PD de ciency who required longer ventilatory support and ICU care compared to 11 matched controls. Given the role of G6PD in altering redox homeostasis 10 , we hypothesize that the de ciency further enhances oxidative stress by uncontrolled production of reactive oxygen species (ROS) during this rapidly evolving in ammation caused by the SARS-CoV-2 virus and host immune system, leading to abnormal pulmonary vascular performance and respiratory decline. This case series warrants a systematic investigation of the role played by G6PD in unrelenting COVID19-induced pneumonitis.…”

<p>Downregulation of miR-7-5p Inhibits the Tumorigenesis of Esophagus Cancer via Targeting KLF4</p>

“…32 It has been regarded that p38 can activate MAPK to promote the cancer development and progression. [33][34][35] In addition, previous studies have confirmed the association between KLF4 and MAPK/p38 signaling. 36,37 Our study further verified the relation between KLF4 and MAPK/p38, suggesting that KLF4 could at as a key modulator on MAPK/ p38 signaling.…”

Inflammasome and Mitophagy Connection in Health and Disease

“…Indeed, the inflammasome activation is tightly regulated by a number of factors at the transcriptional level [ 31 ]. In addition to NF-κB activation, interferon regulatory factor 1 (IRF1), AP-1, and other transcriptional factors are involved in the transcriptional regulation of the components of NLRP3 inflammasome assembly [ 31 , 34 , 35 ]. These priming signals also induce post-translational modifications for several inflammasome components, i.e., NLRP3 deubiquitination and the ubiquitination and phosphorylation of ASC, for further activation of inflammasome complex assembly [ 36 ].…”