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

Abstract

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.

Role of the p38 MAPK/C/EBPβ Pathway in the Regulation of Phenotype and IL-10 and IL-12 Production by Tolerogenic Bone Marrow-Derived Dendritic Cells

“…However, p38 MAPK inhibition led to an increased production of IL-12p70 that was comparable to that of IL-4/DCs. Our data are in line with the report that showed that C5aR inhibited the pro-inflammatory potential of a very pro-inflammatory human DC subset (slanDCs) and induced IL-10 production by initiating and prolonging ERK and p38 MAPK phosphorylation as well as CREB phosphorylation [67]. Furthermore, inhibition of ERK1/2 or p38 MAPK phosphorylation or inhibition of signal transduction upstream of CREB1 (via MSK1/2 inhibition) abrogated the ability of C5aR to induce IL-10 gene expression in LPS-stimulated moDCs.…”

Maturing Human CD127+ CCR7+ PDL1+ Dendritic Cells Express AIRE in the Absence of Tissue Restricted Antigens

“…To determine whether eTACs represent activated and mature DCs, we compared the transcriptomes of eTACs and cDCs with those of unstimulated and LPS-stimulated monocyte-derived DCs (designated moDC), from Zaal et al (17). After controlling for experimental variation using surrogate variable analysis, we compared these DCs to our tonsil-derived cDCs and eTACs in a reduced dimensional space defined by PCA (Figure 5C).…”

The complex functioning of the complement system in xenotransplantation

“…40 C1q, iC3b, C5a-C5aR, CR1, and factor H are reported to regulate the maturation and function of DCs. 24,25,[55][56][57] CR2 is part of the co-receptor (along with CD19, CD81, and Leu13) of B lymphocytes. 58,59 In the germinal centers, C3 degradation fragment-coated immune complexes are recognized and retained by follicular DCs, enhancing the differentiation of memory and effector B cells.…”

“…Antigen‐presenting DCs are critical in adaptive immune defense, and their function is influenced by complement . C1q, iC3b, C5a‐C5aR, CR1, and factor H are reported to regulate the maturation and function of DCs …”