TLR-Induced IL-12 and CCL2 Production by Myeloid Cells Is Dependent on Adenosine A3 Receptor–Mediated Signaling

Abstract

TLR-induced signaling potently activates cells of the innate immune system and is subject to regulation at different levels. Inflammatory conditions are associated with increased levels of extracellular adenosine, which can modulate TLR-induced production of cytokines through adenosine receptor–mediated signaling. There are four adenosine receptor subtypes that induce different signaling cascades. In this study, we demonstrate a pivotal contribution of adenosine A3 receptor (A3R)–mediated signaling to the TLR4-induced expression of IL-12 in different types of human myeloid APC. In dendritic cells, IL-12 and CCL2 responses as evoked by TLR2, 3, 4, 5, and 8, as well as IL-12 responses evoked by whole pathogens, were all reduced when A3R-mediated signaling was blocked. As a result, concomitant production of IFN-γ and IL-17 by T cells was significantly inhibited. We further show that selective inhibition of A3R-mediated signaling reduced TLR-induced phosphorylation of the transcription factor STAT1 at tyrosine 701. Next-generation sequencing revealed that A3R-mediated signaling controls the expression of metallothioneins, known inhibitors of STAT1 phosphorylation. Together our results reveal a novel regulatory layer of innate immune responses, with a central role for metallothioneins and autocrine/paracrine signaling via A3Rs.

NAD+-consuming enzymes in immune defense against viral infection

“…NAMPT, the rate-limiting enzyme in the salvage pathway, is up-regulated by several different viruses, including HIV and Zika virus [ 147 , 148 ]. Searching publicly available microarray and next-generation sequencing data revealed that NAMPT transcription is significantly up-regulated during many immune-related processes, such as myeloid differentiation [ 149 ], lipopolysaccharide (LPS) treatment [ 150 , 151 ], and T cell activation [ 152 ]. This transcriptional data is consistent with the idea that under infections, NAD + biosynthesis needs to be increased.…”

Identification of Potential Risk Genes and the Immune Landscape of Idiopathic Pulmonary Arterial Hypertension via Microarray Gene Expression Dataset Reanalysis

“…The role of this receptor in the pathophysiology of inflammation is complex. Putten et al [60] pointed out that A3R-mediated signaling induced proinflammatory cytokines, while another study showed the protective effect of preventing excessive immune response and immune-mediated damage after A3R activation [61]. To date, research on downregulated ADORA3 and IPAH pathogenesis is insufficient, and the underlying mechanisms still need to be explored.…”

Modulation of myeloid cells by adenosine signaling

“…In immature human dendritic cells adenosine can stimulate A1 and A3 receptor to increase Ca ++ mobilization and actin polymerization, which were associated with increased chemotaxis [52]. Stimulation of A3 receptors in the presence of various inflammatory stimuli through different TLR receptors or in the presence of whole pathogens also promotes IL-12 secretion [53]. A3 signaling was also important for DC-mediated polarization of T cells into Th1 or Th17 phenotypes [53].…”

“…Stimulation of A3 receptors in the presence of various inflammatory stimuli through different TLR receptors or in the presence of whole pathogens also promotes IL-12 secretion [53]. A3 signaling was also important for DC-mediated polarization of T cells into Th1 or Th17 phenotypes [53]. In mature human or mouse dendritic cells; however, adenosine signaling suppresses IL-12 production [54,55].…”