Sirtuins (SIRT1-7) are
NAD(+)-dependent histone deacetylases (HDACs) that play an important role in the control of metabolism and proliferation and the development of age-associated diseases like oncologic, cardiovascular and
neurodegenerative diseases.
Cambinol was originally described as a compound inhibiting the activity of
SIRT1 and
SIRT2, with efficient anti-
tumor activity in vivo. Here, we studied the effects of
cambinol on microbial sensing by mouse and human immune cells and on host innate immune responses in vivo.
Cambinol inhibited the expression of
cytokines (TNF, IL-1β, IL-6, IL-12p40, and IFN-γ), NO and CD40 by macrophages, dendritic cells, splenocytes and whole blood stimulated with a broad range of microbial and
inflammasome stimuli.
Sirtinol, an inhibitor of
SIRT1 and
SIRT2 structurally related to
cambinol, also decreased macrophage response to TLR stimulation. On the contrary, selective inhibitors of
SIRT1 (EX-527 and CHIC-35) and
SIRT2 (AGK2 and AK-7) used alone or in combination had no inhibitory effect, suggesting that
cambinol and
sirtinol act by targeting more than just
SIRT1 and
SIRT2.
Cambinol and
sirtinol at anti-inflammatory concentrations also did not inhibit SIRT6 activity in in vitro assay. At the molecular level,
cambinol impaired stimulus-induced phosphorylation of MAPKs and upstream
MEKs. Going well along with its powerful anti-inflammatory activity,
cambinol reduced TNF blood levels and
bacteremia and improved survival in preclinical models of endotoxic
shock and
septic shock. Altogether, our data suggest that pharmacological inhibitors of
sirtuins structurally related to
cambinol may be of clinical interest to treat inflammatory diseases.