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

Abstract

Adjuvant formulations boost humoral responses by acting through several, yet incompletely elucidated pathways. In this study, we show that oligomycin or 5-aminoimidazole-4-carboxamide-1-β-d-ribonucleoside (AICAR) enhances Ab production when coinjected with T cell-dependent Ags. Oligomycin and AICAR lead to intracellular ATP reduction, suggesting that metabolic stress could be sensed by immune cells and leads to increased humoral responses. AICAR promotes IL-4 and IL-21 by naive Th cells but does not affect dendritic cell activation/maturation in vitro or in vivo. Accordingly, the adjuvant effect of AICAR or oligomycin does not require MyD88 or caspase-1 expression in vivo. Because AICAR is well tolerated in humans, this compound could represent a novel and safe adjuvant promoting humoral responses in vivo with a minimal reactogenicity.

A Comparative Study of Stress-mediated Immunological Functions with the Adjuvanticity of Alum

“…Immunization of mice with the three stress-inducing agents elicited OVAspecific CD4 ϩ T cells responses and antibody production. These findings are consistent with stress exerting adjuvanticity, as has also been reported recently with an antibiotic (Oligomycin), which elicits metabolic stress and adjuvanticity (19).…”

“…Intracellular stress sensors activate inflammasomes and the production of IL-1␤ (17). Metabolic stress is also associated with NLRP3 inflammasomes in type 2 diabetes (18) but can be independent of inflammasomes (19). Intracellular sensors involve NLR (nucleotide-binding oligomerization domain-like receptors), which sense endogenous danger signals (20).…”

AMP kinase promotes Bcl6 expression in both mouse and human T cells

“…injected with 100 μg NP (27) -KLH (Biosearch Technologies) and were sacrificed at the indicated day. For AICAR NP-KLH immunization, 5–10 mg AICAR (Sigma-Aldrich) was mixed with 100 μg NP (27) –KLH in PBS and the mixture was injected i.p., similarly to Andris et al (Andris et al 2011). …”

“…To our knowledge, the data here is the first data linking Bcl6 and AMPK in T cells. Previously, it was shown that AICAR could act as an adjuvant in mice to enhance Ab responses, however T FH cell responses were not specifically analyzed in this study (Andris et al 2011). We therefore repeated this experiment, by injecting mice with the antigen Keyhole Limpet Hemocyanin (KLH) either with or without AICAR.…”

Stress-activated Dendritic Cells (DC) Induce Dual Interleukin (IL)-15- and IL1β-mediated Pathways, Which May Elicit CD4+ Memory T Cells and Interferon (IFN)-stimulated Genes

“…Intracellular stress sensors activate inflammasomes and the production of IL-1␤ (18,19). Metabolic stress is also associated with NLRP3 inflammasomes in type 2 diabetes (20) but can be independent of inflammasomes (21). Intracellular sensors involve NLR (nucleotide-binding oligomerization domain-like receptors), which sense endogenous danger signals (22), released from damaged or necrotic cells, such as HSP70, termed damage-associated molecular patterns.…”