Elevated levels of damage-associated molecular patterns HMGB1 and S100A8/A9 coupled with toll-like receptor-triggered monocyte activation are associated with inflammation in patients with myelofibrosis.

Inflammation plays a pivotal role in the pathogenesis of primary and post-essential thrombocythemia or post-polycythemia vera myelofibrosis (MF) in close cooperation with the underlying molecular drivers. This inflammatory state is induced by a dynamic spectrum of inflammatory cytokines, although recent evidence points to the participation of additional soluble inflammatory mediators. Damage-associated molecular patterns (DAMPs) represent endogenous signals released upon cell death or damage which trigger a potent innate immune response. We assessed the contribution of two prototypical DAMPs, HMGB1 and S100A8/A9, to MF inflammation. Circulating HMGB1 and S100A8/A9 were elevated in MF patients in parallel to the degree of systemic inflammation and levels increased progressively during advanced disease stages. Patients with elevated DAMPs had higher frequency of adverse clinical features, such as anemia, and inferior survival, suggesting their contribution to disease progression. Monocytes, which are key players in MF inflammation, were identified as a source of S100A8/A9 but not HMGB1 release, while both DAMPs correlated with cell death parameters, such as serum LDH and cell-free DNA, indicating that passive release is an additional mechanism leading to increased DAMPs. HMGB1 and S100A8/A9 promote inflammation through binding to Toll-like receptor (TLR) 4, whereas the former also binds TLR2. Monocytes from MF patients were shown to be hyperactivated at baseline, as reflected by higher CD11b and tissue factor exposure and increased expression levels of proinflammatory cytokines IL-1ß and IL-6. Patient monocytes showed preserved TLR4 and TLR2 expression and were able to mount normal or even exacerbated functional responses and cytokine upregulation following stimulation of TLR4 and TLR2. Elevated levels of endogenous TLR ligands HMGB1 and S100A8/A9 coupled to the finding of preserved or hyperreactive TLR-triggered responses indicate that DAMPs may promote monocyte activation and cytokine production in MF, fueling inflammation. Plasma IL-1ß and IL-6 were elevated in MF and correlated with DAMPs levels, raising the possibility that DAMPs could contribute to cytokine generation in vivo. In conclusion, this study highlights that, in cooperation with classic proinflammatory cytokines, DAMPs represent additional inflammatory mediators that may participate in the generation of MF inflammatory state, potentially providing novel biomarkers of disease progression and new therapeutic targets.

Impacto do tratamento na expressão de S100A8/A9 na saliva de pacientes com doença peri-implantar / Impact of treatment on S100A8 / A9 expression in saliva of patients with peri-implant disease

O objetivo do presente estudo foi avaliar o impacto do tratamento na expressão do heterodímero S100A8/A9 e nos parâmetros clínicos em pacientes com mucosite peri-implantar e peri-implantite. Quarenta e sete pacientes foram avaliados e divididos em dois grupos: (1) Mucosite peri-implantar (n=27) e (2) Peri-implantite (n=20). Os parâmetros clínicos avaliados foram: profundidade de bolsa (PB), nível de inserção clínica (NIC), porcentagem de placa (%placa) e sangramento à sondagem (%sangramento). A saliva não estimulada foi coletada na consulta inicial (T0) e três meses após o tratamento (T1). A mucosite peri-implantar foi tratada com raspagem supra gengival e profilaxia; a peri-implantite com terapia cirúrgica ressectiva. Os níveis de S100A8/A9 foram mensurados através do ELISA. Os resultados das características clínicas de boca toda demonstraram que, no grupo 1, houve redução significativa na PB (p=0,001), %placa (p=0,005) e %sangramento (p<0,001) e não no NIC (p=0,740) após o tratamento. No grupo 2, houve redução significativa em PB(p<0,001) e %sangramento (p=0,001) após o tratamento, o que não aconteceu no NIC(p=702) e %placa (p=0,469). Nos parâmetros peri-implantares do grupo 1, houve redução da PB (p<0,001), NIC (p<0,001), %placa (p=0,022) e %sangramento (p<0,001). No grupo 2, também houve redução significativa em PB (p=0,02), %placa (p=0,017), %sangramento (p=0,002) e não houve diferença no NIC(p=0,052). A análise imunológica revelou que, após o tratamento, houve redução significativa na expressão de S100A8/A9 na mucosite peri-implantar (p=0,004) e na peri-implantite (p=0,010). Nas consultas de T0 (p=0,153) e T1 (p=0,982), não houve diferença signitificativa nessa expressão entre o grupo 1 e grupo 2. Assim, pôde-se concluir que o tratamento foi eficaz, uma vez que houve melhora clínica significante dos parâmetros clinicos e redução significativa na expressão de S100A8/A9 na saliva após o tratamento (AU)

We aimed to evaluate the impact of treatment on S100A8 / A9 heterodimer expression in patients with peri-implant mucositis and peri-implantitis. Forty-seven patients were evaluated and divided into two groups: (1) Peri-implant mucositis, with a mean age (MI) of 63.1 years (Standard Deviation [SD] ± 7.7) and (2) Peri-implantitis with MI 61.2 (SD ± 7.0). The clinical parameters evaluated were: pocket depth (PD), clinical attachment level (CAL), percentage of visible plaque (%plaque), and percentage of bleeding on probing (%bleeding). Unstimulated whole saliva was collected at baseline (T0) and three months after treatment (T1). Peri-implant mucositis was treated with supra-gingival scaling and prophylaxis. Peri-implantitis was treated with open flap debridement. S100A8 / A9 levels were measured by ELISA. Our results showed that, in the mucositis group, there was a significant reduction in PD (p=0.001),% plaque (p=0.005) and % bleeding (p <0.001) after treatment. In the peri-implantitis group, there was a significant reduction in PD (p <0.001) and % bleeding (p=0.001) after treatment. Regrading only the Peri-implant parameters, the mucositis group showed a reduction in PD (p <0.001), CAL (p <0.001), %plaque (p=0.022) and %bleeding (p<0.001). In Peri-implantitis group, there was also a significant reduction in PD (p=0.02), %plaque (p=0.017), and % bleeding (p=0.002). S100A8/A9 expression reduced significantly after treatment both in peri-implant mucositis (p=0.004) and peri-implantitis (p=0.010). Therefore, we concluded that the treatment was effective to improve the clinical parameters and to reduce significantly the expression of S100A8 / A9 in patients having peri-implant diseases (AU)