Impaired respiratory burst contributes to infections in PKCδ-deficient patients

Abstract

Patients with autosomal recessive protein kinase C δ (PKCδ) deficiency suffer from childhood-onset autoimmunity, including systemic lupus erythematosus. They also suffer from recurrent infections that overlap with those seen in patients with chronic granulomatous disease (CGD), a disease caused by defects of the phagocyte NADPH oxidase and a lack of reactive oxygen species (ROS) production. We studied an international cohort of 17 PKCδ-deficient patients and found that their EBV-B cells and monocyte-derived phagocytes produced only small amounts of ROS and did not phosphorylate p40phox normally after PMA or opsonized Staphylococcus aureus stimulation. Moreover, the patients’ circulating phagocytes displayed abnormally low levels of ROS production and markedly reduced neutrophil extracellular trap formation, altogether suggesting a role for PKCδ in activation of the NADPH oxidase complex. Our findings thus show that patients with PKCδ deficiency have impaired NADPH oxidase activity in various myeloid subsets, which may contribute to their CGD-like infectious phenotype.

Protein Kinase C Delta Regulates Mononuclear Phagocytes and Hinders Response to Immunotherapy in Cancer

“…PKCδ is a serine/threonine kinase of the novel PKC sub-family and can be activated by stimulation with diacylglycerol leading to PKCδ phosphorylation and activation of downstream targets 24 . PKCδ is involved in a myriad of cellular processes involving apoptosis, proliferation, and cell survival in a variety of cell types including immune cells 24,25 . In the hematopoietic compartment, studies have shown that genetic deletion of PKCδ resulted in systemic autoimmunity which correlated with accumulation of autoreactive B cells in PKCδ knockout mice 26,27 .…”

“…In the hematopoietic compartment, studies have shown that genetic deletion of PKCδ resulted in systemic autoimmunity which correlated with accumulation of autoreactive B cells in PKCδ knockout mice 26,27 . Similarly, patients with autosomal recessive PKCδ deficiency were severely autoimmune and suffered from systemic lupus erythematosus 25 . In myeloid cells, previous work demonstrated that loss of PKCδ resulted in a defective reactive oxygen species production and impaired extracellular trap formation in neutrophils 28 and decreased macrophage phagosomal clearance of Listeria monocytogenes and Mycobacterium tuberculosis 29,30 .…”

“…Protein kinase C delta (PKCδ), a serine/threonine kinase, is involved in several cellular processes including differentiation, apoptosis, cell survival and proliferation 24,25 . Autosomal recessive PKCδ deficiency in humans or genetic deletion of PKCδ in mice resulted in severe systemic autoimmunity 25,26,27 . In myeloid cells, loss of PKCδ resulted in impaired extracellular trap formation in neutrophils 28 and decreased macrophage phagosomal clearance of microbes 29,30 .…”

“…Protein kinase C delta (PKCδ), a serine/threonine kinase, is involved in several cellular processes including differentiation, apoptosis, cell survival and proliferation 24,25 . Autosomal recessive PKCδ deficiency in humans or genetic deletion of PKCδ in mice resulted in severe systemic autoimmunity 25,26,27 .…”

The chemorepellent, SLIT2, bolsters innate immunity againstStaphylococcus aureus

“…The phagocyte oxidative burst is a powerful tool for host defense against versatile pathogens such as S. aureus ( 5, 6 ). The oxidative burst can be further enhanced by priming agents, including tumor necrosis factor-α, which increase ROS production in response to secondary activating stimuli but have no effect on their own ( 28 ).…”