Innate signaling by the C-type lectin DC-SIGN dictates immune responses

Abstract

Effective immune responses depend on the recognition of pathogens by dendritic cells (DCs) through pattern recognition receptors (PRRs). These receptors induce specific signaling pathways that lead to the induction of immune responses against the pathogens. It is becoming evident that C-type lectins are also important PRRs. In particular, the C-type lectin DC-SIGN has emerged as a key player in the induction of immune responses against numerous pathogens by modulating TLR-induced activation. Recent reports have begun to elucidate the molecular mechanisms underlying these immune responses. Upon pathogen binding, DC-SIGN induces an intracellular signaling pathway with a central role for the serine/threonine kinase Raf-1. For several pathogens that interact with DC-SIGN, including Mycobacterium tuberculosis and HIV-1, Raf-1 activation leads to acetylation of NF-kappaB subunit p65, which induces specific gene transcription profiles. In addition, other DC-SIGN-ligands induce different signaling pathways downstream of Raf-1, indicating that DC-SIGN-signaling is tailored to the pathogen. In this review we will discuss in detail the current knowledge about DC-SIGN signaling and its implications on immunity.

Fig. 1

DC-SIGN signaling by mycobacteria, viruses and fungi. Binding of several pathogens including M. tuberculosis, C. albicans and HIV-1 to DC-SIGN activates three routes that converge to activate Raf-1: activation of Ras leads to binding to Raf-1 and induces conformational changes that allow for subsequent phosphorylation of Raf-1 by Src and Pak kinases; Src kinases induce the phosphorylation of Raf-1 at residue Tyr340/341, whereas Rho GTPase-dependent activation of Pak kinases results in phosphorylation of Raf-1 at Ser338. After translocation of NF-κB by TLR-stimulation, DC-SIGN-induced Raf-1 activation mediates the phosphorylation of NF-κB subunit p65 at Ser276, which in turn leads to p65-acetylation. Acetylation of p65 both prolongs and increases IL-10 transcription, resulting in increased IL-10 production

Fig. 2

DC-SIGN signaling by Salp15. Salp15 from tick saliva modulates immune responses to tick-transmitted pathogens such as B. burgdorferi. Salp15 binding to DC-SIGN activates Raf-1 kinase similar as described for pathogens. However, in contrast to DC-SIGN-induced Raf-1 activation by pathogens, Salp15-induced Raf-1 activation leads to activation of MEK. Salp15-induced Raf-1/MEK signaling regulates cytokine expression at different levels: inhibition of IL-6 and TNFα is caused by enhanced degradation of their respective mRNAs, while decreased production of IL-12 results from impaired nucleosome remodeling at the IL-12p35 promoter