5-Aminoimidazole-4-Carboxamide Ribonucleoside: A Novel Immunomodulator with Therapeutic Efficacy in Experimental Autoimmune Encephalomyelitis

Abstract

Experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis, is a Th1-mediated inflammatory demyelinating disease of the CNS. AMP-activated protein kinase was reported recently to have anti-inflammatory activities by negatively regulating NF-κB signaling. In this study, we investigated the prophylactic and therapeutic efficacy of an AMP-activated protein kinase activator, 5-aminoimidazole-4-carboxamide ribonucleoside (AICAR), in active and passive EAE induced by active immunization with PLP139–151 or MOG35–55 and in adoptive transfer of PLP139–151-sensitized T cells, respectively. In vivo treatment with AICAR exerted both prophylactic and therapeutic effects on EAE, attenuating the severity of clinical disease. The anti-inflammatory effects of AICAR were associated with the inhibition of the Ag-specific recall responses and inhibition of the Th1-type cytokines IFN-γ and TNF-α, whereas it induced the production of Th2 cytokines IL-4 and IL-10. Treatment of PLP139–151-specific T cells in vitro with AICAR decreased their expression of T-bet in response to IL-12, a Th1 transcription factor, whereas in response to IL-4, it induced the expression and phosphorylation of Th2 transcription factors GATA3 and STAT6, respectively. Moreover, treatment of APCs in vitro with AICAR inhibited their capability to present the proteolipid protein peptide to PLP139–151-specific T cells. In an irrelevant Th1-mediated, OT-2 TCR transgenic mouse model, AICAR impaired in vivo Ag-specific expansion of CD4+ T cells. Together, these findings show for the first time that AICAR is a novel immunomodulator with promising beneficial effects for the treatment of multiple sclerosis and other Th1-mediated inflammatory diseases.

Metabolic Stress Boosts Humoral Responses In Vivo Independently of Inflammasome and Inflammatory Reaction

“…In that study, AICAR was found to inhibit secretion of the Th1 type cytokines IFN-g and TNF-a while promoting the production of the Th2 cytokines IL-4 and IL-10. Although we have not observed strong inhibition of the Th1 response in our in vitro settings, our data are in keeping with studies showing that AICAR might promote anti-inflammatory responses (52)(53)(54)(55)(56) and suggest that humoral responses could be induced in vivo in the absence of inflammatory reaction.…”

AMP-activated Kinase (AMPK) Promotes Innate Immunity and Antiviral Defense through Modulation of Stimulator of Interferon Genes (STING) Signaling

“…AMPK activators such as AICAR, metformin, and resveratrol, have been linked to antiinflammatory activities through inhibition of NF-B signaling (54 -56) and AMPK activation causes up-regulation of the negative regulatory protein Small Heterodimer Partner (also known as NR0B2) (57). From a clinical standpoint, AICAR may be able to mitigate allergy or other lung injuries by reducing airway inflammation (58,59) and it has also been shown to attenuate the severity of experimental autoimmune encephalitis in mouse models of multiple sclerosis (60,61). Yet, despite these studies, the role of AMPK in immunity is not exclusively anti-inflammatory.…”

Immunomodulatory Effect of Combination Therapy with Lovastatin and 5-Aminoimidazole-4-Carboxamide-1-β-d-Ribofuranoside Alleviates Neurodegeneration in Experimental Autoimmune Encephalomyelitis

“…22 In animal models of endotoxemia 23 and EAE, 22 AICAR treatment protected against lipopolysaccharideinduced proinflammatory response in CNS glial cells as well as in remitting-relapsing EAE in SJL mice. Treatment of EAE mice with AICAR biased myelin-reactive T cells toward Th2 differentiation and was immunomodulatory in antigen-presenting cells via induction of anti-inflammatory cytokines.…”