HMGB1/RAGE Signaling and Pro-Inflammatory Cytokine Responses in Non-HIV Adults with Active Pulmonary Tuberculosis

Abstract

BackgroundWe aimed to study the pathogenic roles of High-Mobility Group Box 1 (HMGB1) / Receptor-for-Advanced-Glycation-End-products (RAGE) signaling and pro-inflammatory cytokines in patients with active pulmonary tuberculosis (PTB).MethodsA prospective study was conducted among non-HIV adults newly-diagnosed with active PTB at two acute-care hospitals (n = 80); age-and-sex matched asymptomatic individuals (tested for latent TB) were used for comparison (n = 45). Plasma concentrations of 8 cytokines/chemokines, HMGB1, soluble-RAGE, and transmembrane-RAGE expressed on monocytes/dendritic cells, were measured. Gene expression (mRNA) of HMGB1, RAGE, and inflammasome-NALP3 was quantified. Patients’ PBMCs were stimulated with recombinant-HMGB1 and MTB-antigen (lipoarabinomannan) for cytokine induction ex vivo.ResultsIn active PTB, plasma IL-8/CXCL8 [median(IQR), 6.0(3.6–15.1) vs 3.6(3.6–3.6) pg/ml, P<0.001] and IL-6 were elevated, which significantly correlated with mycobacterial load, extent of lung consolidation (rs +0.509, P<0.001), severity-score (rs +0.317, P = 0.004), and fever and hospitalization durations (rs +0.407, P<0.001). IL-18 and sTNFR1 also increased. Plasma IL-8/CXCL8 (adjusted OR 1.12, 95%CI 1.02–1.23 per unit increase, P = 0.021) and HMGB1 (adjusted OR 1.42 per unit increase, 95%CI 1.08–1.87, P = 0.012) concentrations were independent predictors for respiratory failure, as well as for ICU admission/death. Gene expression of HMGB1, RAGE, and inflammasome-NALP3 were upregulated (1.2−2.8 fold). Transmembrane-RAGE was increased, whereas the decoy soluble-RAGE was significantly depleted. RAGE and HMGB1 gene expressions positively correlated with cytokine levels (IL-8/CXCL8, IL-6, sTNFR1) and clinico-/radiographical severity (e.g. extent of consolidation rs +0.240, P = 0.034). Ex vivo, recombinant-HMGB1 potentiated cytokine release (e.g. TNF-α) when combined with lipoarabinomannan.ConclusionIn patients with active PTB, HMGB1/RAGE signaling and pro-inflammatory cytokines may play important roles in pathogenesis and disease manifestations. Our clinico-immunological data can provide basis for the development of new strategies for disease monitoring, management and control.

Household Contacts of Leprosy Patients in Endemic Areas Display a Specific Innate Immunity Profile

“…S100A12 has a dual role inducing both proinflammatory and antimicrobial effects by interacting with different receptors, such as RAGE and TLR4 (28). RAGE expression is associated with disease severity and levels of proinflammatory cytokines in active tuberculosis (TB) (29). Contrary, RAGE is protective against the development of pulmonary TB in mouse models (30) in line with reduction of antimicrobial activity in human macrophages upon TLR2/1 ligand activation by S100A12 knockdown (20).…”

Immune responses in the treatment of drug-sensitive pulmonary tuberculosis with phenylbutyrate and vitamin D3 as host directed therapy

“…TB is a chronic infectious disease with a spectrum of symptoms and presentations, wherein cytokines and chemokines play important roles in manipulation of the immune responses, containment of Mtb , pathogenesis and disease manifestations. Various studies have compared serum cytokine/chemokine profiles of patients with different clinical presentations of TB, to establish the expression levels as early surrogate biomarkers of therapeutic responses, bacteriological confirmation of TB and sputum culture conversion [ 31 – 33 ]. We measured cytokines and chemokines in culture supernatants of PBMC instead of serum or plasma, and the findings were similar to previous studies, showing marked decline of serum cytokine/chemokine concentrations at different treatment stages [ 14 , 33 – 37 ].…”

“…Various studies have compared serum cytokine/chemokine profiles of patients with different clinical presentations of TB, to establish the expression levels as early surrogate biomarkers of therapeutic responses, bacteriological confirmation of TB and sputum culture conversion [ 31 – 33 ]. We measured cytokines and chemokines in culture supernatants of PBMC instead of serum or plasma, and the findings were similar to previous studies, showing marked decline of serum cytokine/chemokine concentrations at different treatment stages [ 14 , 33 – 37 ]. Particularly we found that compared to conventional anti-TB treatment in the placebo group, cytokine/chemokine reduction was greater in the PBA or vitD 3 groups that occurred in parallel to clinical recovery [ 25 ] (reduced TB score), suggesting a role of PBA and vitD 3 in dampening of inflammatory responses.…”

“…Notably, the combined treatment with PBA and vitD 3 of the patients exhibited the fastest sputum culture conversion [ 25 ]. Another limitation was that we measured cytokines and chemokines in saponin-treated cell culture fluid instead of serum or plasma as traditionally done [ 10 – 14 , 31 – 33 ]. Measurement of cytokines in the serum does not accurately reflect active secretion of cytokines due to an ongoing infection; moreover it is affected by clearance from the circulation.…”

RNA Sensing of Mycobacterium tuberculosis and Its Impact on TB Vaccination Strategies

“…Another possible approach for further research on endosomal RNA-sensing of MTB could be the receptor for advanced glycation end products (RAGE), which has been found to enhance, among others, endosomal RNA transport of extracellular RNA [44]. Human DCs and monocytes during active TB exhibited an increase in RAGE expression on cell membranes [45], and among a Brazilian TB cohort, levels of soluble RAGE were higher than in healthy controls [46].…”