C-Type Lectin DC-SIGN Modulates Toll-like Receptor Signaling via Raf-1 Kinase-Dependent Acetylation of Transcription Factor NF-κB

Abstract

Adaptive immune responses by dendritic cells (DCs) are critically controlled by Toll-like receptor (TLR) function. Little is known about modulation of TLR-specific signaling by other pathogen receptors. Here, we have identified a molecular signaling pathway induced by the C-type lectin DC-SIGN that modulates TLR signaling at the level of the transcription factor NF-kappaB. We demonstrated that pathogens trigger DC-SIGN on human DCs to activate the serine and threonine kinase Raf-1, which subsequently leads to acetylation of the NF-kappaB subunit p65, but only after TLR-induced activation of NF-kappaB. Acetylation of p65 both prolonged and increased IL10 transcription to enhance anti-inflammatory cytokine responses. We demonstrated that different pathogens such as Mycobacterium tuberculosis, M. leprae, Candida albicans, measles virus, and human immunodeficiency virus-1 interacted with DC-SIGN to activate the Raf-1-acetylation-dependent signaling pathway to modulate signaling by different TLRs. Thus, this pathway is involved in regulation of adaptive immunity by DCs to bacterial, fungal, and viral pathogens.

CLEC‐2 signaling via Syk in myeloid cells can regulate inflammatory responses

“…However, a marked difference is that in the case of CLEC-2 this appears to be a qualitative effect that impacts selectively on some cytokine genes but not others. In fact, this is most similar to the effect of DC-SIGN triggering in human DCs, which signals to potentiate IL-10 production induced by LPS [45]. The key difference is that the effect of DC-SIGN on IL-10 is mediated through a tyrosine-independent RAF-1-dependent pathway [45] whereas the effect of CLEC-2 crosslinking on IL-10 production depends on the ability of CLEC-2 to signal via the Syk/NFAT pathway.…”

“…In fact, this is most similar to the effect of DC-SIGN triggering in human DCs, which signals to potentiate IL-10 production induced by LPS [45]. The key difference is that the effect of DC-SIGN on IL-10 is mediated through a tyrosine-independent RAF-1-dependent pathway [45] whereas the effect of CLEC-2 crosslinking on IL-10 production depends on the ability of CLEC-2 to signal via the Syk/NFAT pathway. Indeed, using Raf inhibitors, we failed to observe any RAF-1 involvement in CLEC-2 modulation of LPS responses (data not shown).…”

Lack of galectin‐3 alters the balance of innate immune cytokines and confers resistance to Rhodococcus equi infection

“…Indeed other lectins have been shown to cooperate with TLR-driven pathways, culminating in enhanced cytokine production [39,40]. Recently, galectin-3 was found to be coprecipitated with TLR2 in THP-1 cells after incubation with C. albicans blastoconidia, suggesting that galectin-3 may be associated with TLR2 at the membrane and following interaction with the yeast [21].…”

A role of the Ca 2+ binding site of DC-SIGN in the phagocytosis of E. coli

“…This result suggests that the CRD of DC-SIGN is involved in the interaction with E. coli particles. Several lines of evidence on DC-SIGN-mediated signaling pathways have been accumulated [8][9][10]. DC-SIGN is colocalized with the protein-tyrosine kinases Syk and Lyn, Src-family kinases, in lipid raft-enriched microdomain, which are involved in immunoreceptor signaling in lymphoid and myeloid cells [9].…”

“…DC-SIGN is colocalized with the protein-tyrosine kinases Syk and Lyn, Src-family kinases, in lipid raft-enriched microdomain, which are involved in immunoreceptor signaling in lymphoid and myeloid cells [9]. In addition, it has been demonstrated that ligation of DC-SIGN on human DCs induces activation of Raf-1, which subsequently induces acetylation of RelA (p65) of the transcription factor NF-B only after TLR4-induced activation of NF-B [8].…”