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.

BackgroundSLE is an autoimmune condition affecting predominantly women. Little is known regarding Chlamydia trachomatis infection in women with SLE, which may drive autoimmunity and contribute to obstetrical and vascular complications.MethodsThis single-centre, case–control study set primary endpoint in the comparative seropositivity rate to C. trachomatis major outer membrane protein (MOMP) and chlamydial heat-shock protein-60 (cHSP60) in age-matched subjects. The secondary endpoints were obstetrical outcomes, cardiovascular events and results from screening procedures for cervical cancer.ResultsEighty-four women with SLE and 50 age-matched controls were included. Seropositivity to C. trachomatis did not differ significantly between groups (10% of cases positive for anti-MOMP vs 12% of controls; 43% of cases positive for anti-cHSP60 vs 32% of controls). Women with SLE were more often of non-Caucasian ethnicity and had lower educational level. They relied less frequently on oral contraception and resorted more frequently to elective pregnancy termination. Pre-eclampsia and ectopic pregnancy occurred only in SLE. Women with SLE also experienced more cardiovascular events. In SLE, antibodies to cHSP60 were associated with a history of pericarditis and abnormal screening tests for cervical cancer. Antibody titres to C. trachomatis were not associated with disease activity or SLE treatment, nor were there associations with other gynaecological, obstetrical or vascular outcomes.ConclusionPrevalence of antibodies to C. trachomatis was not increased in women with SLE. No significant association was found between these antibodies and obstetrical or cardiovascular complications.

Isolated chronic granulomatous meningitis remains a diagnostic challenge for the physician. Symptoms are often nonspecific and ancillary tests have low-sensitivity rates, which may delay targeted treatment and lead to increased morbidity and mortality. Here, we discuss the challenges in diagnosing and treating patients with chronic meningitis by reporting two cases of previously healthy patients who presented with granulomatous meningitis on brain biopsy.