Adenosine modulates Toll-like receptor function: basic mechanisms and translational opportunities

Abstract

Adenosine is an endogenous purine metabolite whose concentration in human blood plasma rises from nanomolar to micromolar during stress or hypoxia. Leukocytes express seven-transmembrane adenosine receptors whose engagement modulates Toll-like receptor-mediated cytokine responses, in part via modulation of intracellular cyclic adenosine monophosphate (cAMP). Adenosine congeners are used clinically to treat arrhythmias and apnea of prematurity. Herein we consider the potential of adenosine congeners as innate immune response modifiers to prevent and/or treat infection.

Defective B cell tolerance in adenosine deaminase deficiency is corrected by gene therapy

“…All ADA-SCID patients showed central B cell tolerance checkpoint defects before HSC-GT, as illustrated by increased frequencies of polyreactive B cells in their new emigrant/transitional B cell compartment, which suggests that ADA impinges on BCR and/or TLR signaling. Consistent with this hypothesis, adenosine receptor signaling and intracellular cAMP have been reported to modulate BCR and TLR functions (25,26,29,35). Indeed, adenosine blocks NF-κB activation in murine B cells stimulated through BCRs, as well as TLR4 activation by LPS (26,29).…”

“…Human B cells express TLR7 and TLR9 that bind RNA and DNA, respectively, which may be involved in the removal of developing anti-nuclear antibody-expressing (ANA-expressing) B cells (24). Interestingly, both BCR-and TLR-mediated B cell responses seem to be modulated by adenosine receptor signaling and intracellular cAMP, which are both affected by ADA deficiency (25,26). We therefore assessed B cell tolerance checkpoints in ADA-SCID patients by cloning antibodies expressed by single B cells before and after successful HSC-GT.…”

Responsiveness of human monocytes to the commensal bacterium Staphylococcus epidermidis develops late in gestation

“…The defect that results in reduced phagocytosis-induced cytokine responses in infants with very low GA may reflect distinct features of neonatal signaling pathways that blunt cytokine production. Examples of these are relatively high neonatal plasma concentrations of immunomodulatory adenosine and relatively high concentrations of cyclic adenosine monophosphate in MNCs, or other impairments that may lie downstream of nuclear factor-κB activation (30). Of note, we were able to detect some cytokine production in response to SE even in extremely premature infants, further indicating that the MNCs of preterm infants are able to recognize and engage SE bacteria.…”

“…Purified monocytes (>85%) were incubated with the following stimuli; pHrodo-labeled SE bacteria (4 × 10 7 CFU/ml) with 10% baby rabbit complement, 10 ng/ml LPS (Alexis, Lausen, Switzerland), or 100 ng/ml FSL-1 (Invivogen). The cells were harvested by transfer to 2 ml of ice-cold PBS at 15,30, 60, 90, 120, and 150 min. Unstimulated cells and those stimulated with LPS or FSL-1 were incubated only for 30 min.…”

High expression levels of macrophage migration inhibitory factor sustain the innate immune responses of neonates

“…*P < 0.05. levels of cortisol at birth range between 0.07 and 0.8 μM and decrease by 10-fold during the first week of life (11,60). Adenosine and prostaglandins are well-known modulators of immune responses and share some similarities: production by the placenta, different cellular effects depending on the cell type and receptor expression, and the ability to increase intracellular levels of the second messenger cAMP, leading to specific inhibition of LPS-induced TNF production (9,(61)(62)(63)(64)(65). Although a reduction of LPS-induced ERK1/2 and NF-κB activation by adenosine A3 receptor activation has been described in mouse macrophages (39), the pathways modulated by adenosine and PGE 2 have not been investigated downstream of cAMP in human cells (9).…”