Costimulation of Dectin-1 and DC-SIGN Triggers the Arachidonic Acid Cascade in Human Monocyte-Derived Dendritic Cells

Abstract

Inflammatory mediators derived from arachidonic acid (AA) alter the function of dendritic cells (DC), but data regarding their biosynthesis resulting from stimulation of opsonic and nonopsonic receptors are scarce. To address this issue, the production of eicosanoids by human monocyte-derived DC stimulated via receptors involved in Ag recognition was assessed. Activation of FcγR induced AA release, short-term, low-grade PG biosynthesis, and IL-10 production, whereas zymosan, which contains ligands of both the mannose receptor and the human β-glucan receptor dectin-1, induced a wider set of responses including cyclooxygenase 2 induction and biosynthesis of leukotriene C4 and IL-12p70. The cytosolic phospholipase A2 inhibitor pyrrolidine 1 completely inhibited AA release stimulated via all receptors, whereas the spleen tyrosine kinase (Syk) inhibitors piceatannol and R406 fully blocked AA release in response to immune complexes, but only partially blocked the effect of zymosan. Furthermore, anti-dectin-1 mAb partially inhibited the response to zymosan, and this inhibition was enhanced by mAb against DC-specific ICAM-3-grabbing nonintegrin (SIGN). Immunoprecipitation of DC lysates showed coimmunoprecipitation of DC-SIGN and dectin-1, which was confirmed using Myc-dectin-1 and DC-SIGN constructs in HEK293 cells. These data reveal a robust metabolism of AA in human DC stimulated through both opsonic and nonopsonic receptors. The FcγR route depends on the ITAM/Syk/cytosolic phospholipase A2 axis, whereas the response to zymosan involves the interaction with the C-type lectin receptors dectin-1 and DC-SIGN. These findings help explain the distinct functional properties of DC matured by immune complexes vs those matured by β-glucans.

Polarization of the Innate Immune Response by Prostaglandin E2: A Puzzle of Receptors and Signals

“…Similar to the distinct responses observed in the different types of differentiated macrophages, AA metabolism in DCs shows distinct patterns in mature and immature DCs. Whereas the release of AA elicited by some ligands showed no difference between immature and tumor necrosis factor-a (TNFa)-mature cells, an enhanced expression of COX-2 was best observed in immature DCs (Valera et al, 2008), thus highlighting the distinct patterns of response associated with environmental cues. In the case of LPS, DCs express the LPS coreceptor CD14 at lower levels than macrophages (Segura et al, 2013) and this may explain the different intensity of the response.…”

“…The CARD9/MALT/BCL10/TRAF6 complex is also involved in the activation of IkB kinases. This scheme has been constructed from the results reported by Suram et al (2006Suram et al ( , 2010, Valera et al (2008), and Parti et al (2010). DAG, diacylglycerol; IP 3 , inositol 1,4,5-trisphosphate; IRAK, interleukin-1 receptor-associated kinase; MAL, MyD88 adaptor-like; P-Y, phosphotyrosine; ptgs2, COX-2 gene; mpges1, microsomal prostaglandin E synthase-1 gene; TAK1, transforming growth factor-b-activated kinase-1.…”

High Mitochondrial Respiration and Glycolytic Capacity Represent a Metabolic Phenotype of Human Tolerogenic Dendritic Cells

“…Interestingly, our analyses demonstrated that tolerogenic and immature moDCs preferentially expressed FAO genes associated with the mitochondria, in contrast to mature moDCs, which expressed peroxisomal FAO genes. Earlier studies have reported that moDC maturation by LPS induces release of arachidonic acid (25,26), which is in part catabolized by peroxisomal FAO (27)(28)(29).…”

Chloroquine Promotes IL-17 Production by CD4+ T Cells via p38-Dependent IL-23 Release by Monocyte-Derived Langerhans-like Cells

“…Similarly to IL-1b, previous studies revealed a potent IL-23, but low IL-12p70 release in human DC and macrophages, induced by TLR2 activation (28,29). Thus, we used the specific TLR2/1 ligand Pam 3 CSK 4 to activate MoLC and MoDC.…”