Inosine monophosphate and inosine differentially regulate endotoxemia and bacterial sepsis

Abstract

Inosine monophosphate (IMP) is the intracellular precursor for both adenosine monophosphate and guanosine monophosphate and thus plays a central role in intracellular purine metabolism. IMP can also serve as an extracellular signaling molecule, and can regulate diverse processes such as taste sensation, neutrophil function, and ischemia-reperfusion injury. How IMP regulates inflammation induced by bacterial products or bacteria is unknown. In this study, we demonstrate that IMP suppressed tumor necrosis factor (TNF)-α production and augmented IL-10 production in endotoxemic mice. IMP exerted its effects through metabolism to inosine, as IMP only suppressed TNF-α following its CD73-mediated degradation to inosine in lipopolysaccharide-activated macrophages. Studies with gene targeted mice and pharmacological antagonism indicated that A 2A , A 2B, and A 3 adenosine receptors are not required for the inosine suppression of TNF-α production. The inosine suppression of TNF-α production did not require its metabolism to hypoxanthine through purine nucleoside phosphorylase or its uptake into cells through concentrative nucleoside transporters indicating a role for alternative metabolic/uptake pathways. Inosine augmented IL-β production by macrophages in which inflammasome was activated by lipopolysaccharide and ATP. In contrast to its effects in endotoxemia, IMP failed to affect the inflammatory response to abdominal sepsis and pneumonia. We conclude that extracellular IMP and inosine differentially regulate the inflammatory response.

Integrated transcriptomics and metabolomics analysis of the hippocampus reveals altered neuroinflammation, downregulated metabolism and synapse in sepsis-associated encephalopathy

“…Uracil has been shown as the intermediate metabolite to neuroprotection and neuroinflammation ( Lecca and Ceruti, 2008 ). Adenine and pseudouridine could cause inflammation; however, other nucleotides and derivatives (inosine, guanosine, pyridoxamine, and cyclic AMP) have anti-inflammatory effects ( Gerbatin et al, 2017 ; Itokawa et al, 2018 ; Veremeyko et al, 2018 ; Lovaszi et al, 2021 ) that decrease as SAE progresses. This result suggested that the metabolites could not affect the anti-inflammatory response.…”

Metabolic heterogeneity caused by HLA-DRB1*04:05 and protective effect of inosine on autoimmune hepatitis

“…HPLC/MS was used to detect the difference in metabolic profiles between the two g r o u p s . I n o s i n e , r e p o r t e d a s a m e t a b o l i t e w i t h immunomodulatory effects (13,14), was found to be highly altered between the DRB1*04:05 positive and negative groups. There are few reports on inosine in AIH.…”

International Union of Basic and Clinical Pharmacology. CXII: Adenosine Receptors: A Further Update

“…Inosine has been reported by several groups to interact with ARs (e.g., with A 2A AR and A 3 AR) but only at very high, nonphysiologic concentrations (>100 μ M) ( Welihinda et al, 2016 ). On the other hand, inosine ( Lovászi et al, 2021 ) as well as the nucleoside guanosine ( Di Liberto et al, 2016 ) clearly show pharmacological effects, at least some of which seemed to be exerted by interaction with GPCRs. However, it is unlikely that these effects are mediated by direct activation of ARs.…”