Crosstalk between Toll like receptors and C5a receptor in human monocyte derived DCs suppress inflammatory cytokine production

Zaal, Anouk; Lissenberg-Thunnissen, Suzanne N.; Schijndel, Gijs van; Wouters, Diana; Ham, S. Marieke van; Brinke, Anja ten

doi:10.1016/j.imbio.2012.02.014

Cited by 24 publications

(33 citation statements)

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“…TLR4 stimulation strongly induced mRNA expression of pro-inflammatory cytokines by moDC (Figures S6B–D in Supplementary Material) and the reported inhibitory effect of C5a on LPS-induced pro-inflammatory cytokine production by moDC (8) could be confirmed at mRNA level (Figures S6B–D in Supplementary Material; Figure 5C). Whereas C5a-induced IL-10 mRNA expression was not affected by inhibition of IL-10 (Figures 5A,B), the inhibitory effect of C5a on TNFα and IL-12p35 mRNA expression was fully nullified and the inhibitory effect on IL-12p40 mRNA expression was partially abrogated (Figures 5C,D).…”

Section: Resultsmentioning

confidence: 60%

“…Purity of monocytes was confirmed with flow cytometry, and monocytes were cultured at 20 × 10 6 cells in 20 ml Cellgro DC serum-free medium supplemented with penicillin/streptomycin (100 U/ml), GM-CSF (1000 IU/ml), and IL-4 (800 IU/ml) for 7 days at 37°C, 5% CO 2 as described previously (8). After 7 days, moDCs were harvested and rested for 2 h in Cellgro DC serum-free medium supplemented with penicillin/streptomycin (100 U/ml) and 1% FCS at 37°C, 5% CO 2 prior to stimulation.…”

Section: Methodsmentioning

confidence: 99%

“…The complement activation product 5a (C5a) is a well-known chemo-attractant but has also been implicated in modulation of mouse antigen presenting cell function (1–7). We previously demonstrated that crosstalk between C5a receptor (C5aR) and toll-like receptor (TLR) signaling dampens the pro-inflammatory potential of human monocyte-derived dendritic cells (moDCs) by decreasing the production of IL-6, TNF-α, IL-12, and IL-23 (8). This inhibitory effect of C5a on human moDC only occurred on maturing DCs, as in the absence of a TLR stimulus, C5a promoted production of the pro-inflammatory cytokines IL-6, TNF-α, and IL-12 (8, 9).…”

Section: Introductionmentioning

confidence: 99%

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Anaphylatoxin C5a Regulates 6-Sulfo-LacNAc Dendritic Cell Function in Human through Crosstalk with Toll-Like Receptor-Induced CREB Signaling

et al. 2017

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Activation of antigen-presenting dendritic cells (DCs) and the complement system are essential early events in the immune defense against invading pathogens. Recently, we and others demonstrated immunological crosstalk between signaling from receptors recognizing complement activation products and PAMPs on DCs. This affects DC effector function, as demonstrated by the finding that C5a prevents induction of pro-inflammatory cytokines by toll-like receptor (TLR) ligands in human monocyte-derived DCs (moDCs). Here, we demonstrate that this regulatory crosstalk is specifically important in 6-sulfo LacNAc dendritic cells (slanDCs), the most pro-inflammatory DC subset found in human. C5aR and TLR signaling show profound interference in the ERK/p38/CREB1 signaling pathways. C5aR signaling accelerates TLR-induced CREB1 phosphorylation both in moDC and slanDC. This is key in the regulatory effect of C5a on pro-inflammatory DC maturation by mediating induction of IL-10, which subsequently inhibits pro-inflammatory cytokine production via negative feedback signaling. Importantly, the regulatory effect of C5a affects T-cell immunity by decreasing Th1 and cytotoxic CD8 T-cell responses. The finding that the pro-inflammatory effector function of slanDC can be down modulated by activation products of the complement system highlights the existence of intricate regulatory interactions between various arms of the immune system. Intensive immune monitoring of patients suffering from complement-mediated diseases or patients receiving complement modulating compounds can give more inside in the contribution of complement receptor and TLR crosstalk in APCs in disease.

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Section: Resultsmentioning

confidence: 60%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Anaphylatoxin C5a Regulates 6-Sulfo-LacNAc Dendritic Cell Function in Human through Crosstalk with Toll-Like Receptor-Induced CREB Signaling

et al. 2017

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“…39 Thus, the specific effects of C5a on IL-17-driving cytokine production in mouse models is dependent on the antigen-presenting cell type sensing the C5a signal and the TLR that is coengaged; a similar picture emerges for human antigen-presenting cells. 40 Here, we show that C3aR engagement in human monocytes increases the release of TLR4-mediated cytokines, leading to enhanced Th17 responses. We further observed that C5aR engagement, without TLR coactivation, induces a strong IL-6 response in human monocytes.…”

Section: Discussionmentioning

confidence: 70%

C3a modulates IL-1β secretion in human monocytes by regulating ATP efflux and subsequent NLRP3 inflammasome activation

Asgari

Friec

Yamamoto

et al. 2013

Blood

267

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Key Points• C3aR activation increases ATP efflux, NLRP3 inflammasome activation, and IL-1b secretion in human monocytes.• C3aR-activated monocytes drive Th17 responses in vitro and likely in vivo.Interleukin-1b (IL-1b) is a proinflammatory cytokine and a therapeutic target in several chronic autoimmune states. Monocytes and macrophages are the major sources of IL-1b. IL1b production by these cells requires Toll-like receptor (TLR) and adenosine triphosphate (ATP)-mediated P2X purinoceptor 7 (P2X7) signals, which together activate the inflammasome. However, how TLR signals and ATP availability are regulated during monocyte activation is unclear and the involvement of another danger signal system has been proposed. Here, we demonstrate that both lipopolysaccharide (LPS) and the anaphylatoxin C3a are needed for IL-1b production in human macrophages and dendritic cells, while in monocytes, C3a enhanced the secretion of LPS-induced IL-1b. C3a and LPS-stimulated monocytes increased T helper 17 (Th17) cell induction in vitro, and human rejecting, but not nonrejecting, kidney transplant biopsies were characterized by local generation of C3a and monocyte and Th17 cell infiltration. Mechanistically, C3a drives IL-1b production in monocytes by controlling the release of intracellular ATP into the extracellular space via regulation of as-yet unidentified ATPreleasing channels in an extracellular signal-regulated kinase 1/2-dependent fashion. These data define a novel function for complement in inflammasome activation in monocytes and suggest that C3aR-mediated signaling is a vital component of the IL1b-Th17 axis. (Blood. 2013;122(20):3473-3481) IntroductionInterleukin-1b (IL-1b) is a key proinflammatory cytokine involved in host responses to pathogens and tissue injury. IL-1b has gathered substantial interest in recent years because several autoimmune disorders respond specifically to IL-1 receptor blockade using either soluble IL-1 receptor antagonists or blocking monoclonal antibodies (mAbs).1 In addition to inducing neutrophil activation and histamine release by mast cells and maintaining epithelial cell integrity, 2 IL-1b also plays a central role in modulating adaptive effector T-cell responses by preferentially inducing T helper 1 (Th1) and Th17 differentiation.3 In humans, CD4 1 T cells require IL-1b and IL-6 to differentiate into Th17 cells, 4 which contribute to the pathophysiology of inflammatory and autoimmune diseases 5 as well as ischemia reperfusion injury (IRI) and transplant rejection. Monocytes, macrophages, and dendritic cells (DCs) are major IL-1b sources and release this cytokine in response to stimuli such as pathogen-associated or danger-associated molecular patterns (PAMPs or DAMPs) mediated by signaling via several Toll-like receptor (TLR) pathways. 7 Although consensus exists that IL-1b generation requires processing of the 31 K D inactive pro-IL-1b to the 17 K D active form by caspase-1 activation via an inflammasome complex (eg, NLRP3), 8,9 signals leading to NLRP3 and caspase-1 activation are...

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“…C5a-induced suppression of the LPS-inducible IL-17A/IL-23 axis was reported to occur via enhanced IL-10 production and ERK1/2 phosphorylation. However, most studies reporting C5a modulation of TLR4 signaling had been performed with murine rather than human cells (18,19). Some interpretations of human disease mechanisms have been made based on extrapolating from observations of mouse studies.…”

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confidence: 99%

Inflammatory Responses Induced by Lipopolysaccharide Are Amplified in Primary Human Monocytes but Suppressed in Macrophages by Complement Protein C5a

Seow

Lim

Iyer

et al. 2013

The Journal of Immunology

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Monocytes and macrophages are important innate immune cells equipped with danger-sensing receptors, including complement and Toll-like receptors. Complement protein C5a, acting via C5aR, is shown in this study to differentially modulate LPS-induced inflammatory responses in primary human monocytes versus macrophages. Whereas C5a enhanced secretion of LPS-induced IL-6 and TNF from primary human monocytes, C5a inhibited these responses while increasing IL-10 secretion in donor-matched human monocyte-derived macrophages differentiated by GM-CSF or M-CSF. Gαi/c-Raf/MEK/ERK signaling induced by C5a was amplified in macrophages but not in monocytes by LPS. Accordingly, the Gαi inhibitor pertussis toxin and MEK inhibitor U0126 blocked C5a inhibition of LPS-induced IL-6 and TNF production from macrophages. This synergy was independent of IL-10, PI3K, p38, JNK, and the differentiating agent. Furthermore, C5a did not inhibit IL-6 production from macrophages induced by other TLR agonists that are selective for Toll/IL-1R domain–containing adapter inducing IFN-β (polyinosinic-polycytidylic acid) or MyD88 (imiquimod), demonstrating selectivity for C5a regulation of LPS responses. Finally, suppression of proinflammatory cytokines IL-6 and TNF in macrophages did not compromise antimicrobial activity; instead, C5a enhanced clearance of the Gram-negative bacterial pathogen Salmonella enterica serovar Typhimurium from macrophages. C5aR is thus a regulatory switch that modulates TLR4 signaling via the Gαi/c-Raf/MEK/ERK signaling axis in human macrophages but not monocytes. The differential effects of C5a are consistent with amplifying monocyte proinflammatory responses to systemic danger signals, but attenuating macrophage cytokine responses (without compromising microbicidal activity), thereby restraining inflammatory responses to localized infections.

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Crosstalk between Toll like receptors and C5a receptor in human monocyte derived DCs suppress inflammatory cytokine production

Cited by 24 publications

References 26 publications

Anaphylatoxin C5a Regulates 6-Sulfo-LacNAc Dendritic Cell Function in Human through Crosstalk with Toll-Like Receptor-Induced CREB Signaling

Anaphylatoxin C5a Regulates 6-Sulfo-LacNAc Dendritic Cell Function in Human through Crosstalk with Toll-Like Receptor-Induced CREB Signaling

C3a modulates IL-1β secretion in human monocytes by regulating ATP efflux and subsequent NLRP3 inflammasome activation

Inflammatory Responses Induced by Lipopolysaccharide Are Amplified in Primary Human Monocytes but Suppressed in Macrophages by Complement Protein C5a

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