Protein kinase Cδ is a critical component of Dectin-1 signaling in primary human monocytes

Abstract

Zymosan, a mimic of fungal pathogens, and its opsonized form (ZOP) are potent stimulators of monocyte NADPH oxidase, resulting in the production of O(2)(.-), which is critical for host defense against fungal and bacterial pathogens and efficient immune responses; however, uncontrolled O(2)(.-) production may contribute to chronic inflammation and tissue injury. Our laboratory has focused on characterizing the signal transduction pathways that regulate NADPH oxidase activity in primary human monocytes. In this study, we examined the involvement of various pattern recognition receptors and found that Dectin-1 is the primary receptor for zymosan stimulation of O(2)(.-) via NADPH oxidase in human monocytes, whereas Dectin-1 and CR3 mediate the activation by ZOP. Further studies identified Syk and Src as important signaling components downstream of Dectin-1 and additionally identified PKCδ as a novel downstream signaling component for zymosan-induced O(2)(.-) as well as phagocytosis. Our results show that Syk and Src association with Dectin-1 is dependent on PKCδ activity and expression and demonstrate direct binding between Dectin-1 and PKCδ. Finally, our data show that PKCδ and Syk but not Src are required for Dectin-1-mediated phagocytosis. Taken together, our data identify Dectin-1 as the major PRR for zymosan in primary human monocytes and identify PKCδ as a novel downstream signaling kinase for Dectin-1-mediated regulation of monocyte NADPH oxidase and zymosan phagocytosis.

Bruton's Tyrosine Kinase (BTK) and Vav1 Contribute to Dectin1-Dependent Phagocytosis of Candida albicans in Macrophages

“…BTK and Vav1 can now be added to the list of Dectin1-interacting proteins, which includes Syk [4], PKCδ [5], the tetraspanin CD37 [6], Galectin-3 [7] and TLR2 [8]. The multiple interactions of Dectin-1 with its partners reflect the complexity of Dectin-1 signaling and the (sub)complexes in which it participates.…”

“…With multiple Dectin1-interacting proteins identified, the interesting possibility of tripartite or multicomponent signalosomes arises. Dectin-1 multicomponent signalosomes exist, as complexes were found that encompassed PKCδ, Syk and Dectin-1 [5]. We tested the possibility of a Dectin1/BTK/Vav1 tripartite complex, but could not detect the three proteins in a single complex (data not shown).…”

“…The role of Syk in Dectin-1-mediated phagocytosis is cell type-dependent: Syk is essential for phagocytosis in dendritic cells, but not in macrophages [3], [4]. Other proteins that interact with Dectin-1 are PKCδ [5], the tetraspanin CD37 [6], Galectin-3 [7] and TLR2 [8]. Ectopic expression of Dectin-1 in fibroblasts or kidney cells confers phagocytic capacity to these cells [3], [7].…”

Group V Secreted Phospholipase A2 Is Upregulated by IL-4 in Human Macrophages and Mediates Phagocytosis via Hydrolysis of Ethanolamine Phospholipids

“…Macrophages participate in innate immunity reactions by mediating opsonic (IgG-and complement-mediated) or nonopsonic phagocytosis (via pattern-recognition receptors) of invading microorganisms (8)(9)(10)(11). Phagocytosis of foreign material is usually accompanied by the secretion of large amounts of cytokines and AA-derived eicosanoids that, as time passes, contribute to modulate the progress and extent of the inflammatory process.…”

A Phosphatidylinositol Species Acutely Generated by Activated Macrophages Regulates Innate Immune Responses

“…Zymosan is a cell-wall preparation of Saccharomyces cerevisiae that is widely used as a model stimulus for macrophage activation (1)(2)(3)(4)(5)(6). Zymosan is composed of b-glucan, mannans, mannoproteins, and chitin and is recognized by multiple macrophage receptors, including dectin-1, TLR2, complement receptor 3, mannose receptors, and scavenger receptors (7,8).…”