Blocking Innate Immune Receptors: Possible Approach for Chronic Inflammation Treatment

Deena H. Elsori, College of Arts and Sciences, Abu Dhabi University
Valentin Yakubenko, Department of Cell Biology, Cleveland Clinic
Ashish Bhattacharjee, Department of Cell Biology, Cleveland Clinic
Martha K. Cathcart, Ph.D., Department of Cell Biology, Cleveland Clinic

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Macrophages are major participants chronic inflammation. One macrophage activation pathway that is believed to contribute to the pathology of chronic inflammation is the production of superoxide anion via the NADPH oxidase enzyme complex. We hypothesized that in the oxidative environment of a chronic inflammatory site that repetitive ligands might be generated that could trigger further macrophage activation via pattern recognition receptors. Zymosan, a yeast cell wall preparation, is a potent activator of macrophage NADPH oxidase. Our laboratory has focused on characterizing the signal transduction pathways that regulate NADPH oxidase activity in primary human monocytes.  We have previously identified several pathways that regulate the activity of NADPH oxidase; yet, the receptor (s) responsible for Zymosan and ZOP signaling to NADPH oxidase in primary monocytes has not been determined.  We examined the involvement of various pattern recognition receptors and found that Dectin-1 is the primary receptor for Zymosan stimulation of O2.- via NADPH oxidase in human monocytes whereas Dectin-1 and CR3 both mediate the activation by ZOP.  We provide evidence that this activation is independent of TLR2 and TLR4. Additionally, we show that Src and Syk tyrosine kinases regulate Zymosan-induced O2.- production and that blocking Dectin-1 signaling prevents their phosphorylation/activation.  We discovered that Zymosan induces PKCδ and Syk complex formation with Dectin-1 and this event is regulated by PKCδ activity.  Furthermore PKCδ activity was also found to be required for phagocytosis of Zymosan.  Taken together, our data implicate Dectin-1 as an important pattern recognition receptor for Zymosan and ZOP-mediated activation of NADPH oxidase in primary human monocytes and identify PKCδ as a critical downstream signaling pathway for Dectin-1 regulation of both O2.- production and phagocytosis.

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