The monoterpene 1,8-Cineol is a natural plant-based therapeutic agent that is commonly applied to treat different inflammatory diseases due to its mucolytic, anti-microbial and anti-inflammatory properties. It has become increasingly clear in the recent years that 1,8-Cineol spreads almost everywhere in the human body after its oral administration, from the gut to the blood to the brain. Its anti-microbial potential and even its anti-viral effects have been observed to include numerous bacteria and fungi species. Many recent studies help to better understand the cellular and molecular immunological consequences of 1,8-Cineol treatment in inflammatory diseases and further provide information concerning the mechanistic modes of action in the regulation of distinct inflammatory biosynthetic pathways. This review aims to present a holistic and understandable overview of the different aspects of 1,8-Cineol in infections and inflammation.

Obstructive sleep apnea syndrome (OSAS) represents a substantial disease of recurrent sleep fragmentation, leading to intermittent hypoxia and subsequent diseases such as cardiovascular, metabolic, or cognitive dysfunctions. In addition, OSAS is considered as low-grade systemic inflammation, which is associated with a higher incidence of cancer, severity of infections, and an overall immune dysregulation. This research project aims to comprehensively investigate the interplay of wholesome sleep and the immune functions of circulating monocytes and T cells in OSAS patients, which are known to be affected by oxidative stress. We studied the distribution of the CD14/CD16 characterized monocyte subsets in peripheral blood as well as their PD-L1 expression and complex formation with T cells. Furthermore, a detailed analysis of T cell subsets with regard to their PD-1 and PD-L1 expression was performed. Data revealed a decrease of classical monocytes accompanied by an increase of both CD16⁺ monocyte subsets in OSAS patients that was positively correlated with the body mass index. OSAS patients revealed an increased PD-1 and PD-L1 expression in T cells and monocytes, respectively, which was linked to the severity of monocyte subset alterations. The complex formation of monocytes and T cells was also elevated in OSAS patients, which indicates a deregulated PD-1/PD-L1 cross-talk between these cells. Our data show for the first time, to our knowledge, massive alterations of peripheral monocyte subsets in response to OSAS and its accompanying phenomena. Key Points OSAS patients reveal decreased levels of CD14⁺⁺CD16⁻ classical monocytes. Increased monocyte/T cell aggregation occurs in the blood of OSAS patients. Alteration of T cell subsets and PD-1/PD-L1 cross-talk occurs in OSAS patients.

It has been shown that head and neck squamous cell carcinoma (HNSCC) is infiltrated by plasmacytoid dendritic cells (pDCs). The HNSCC TH2 biased microenvironment leads to strong alterations of the cellular functions of pDC and thus impairs the initiation and function of adequate immune responses. In this work we comprehensively analyzed the capacity of CpG‑oligonucleotides to activate interferon (IFN)‑α secretion of human pDC in the presence of HNSCC. IFN‑α secretion was measured using the ELISA Technique. Class A CpG dinucleotide 2216 was used in different concentrations and time frames to stimulate the IFN‑α production of human pDC from peripheral blood in the absence and presence of the HNSCC microenvironment. To elucidate single components that might induce the reduction of IFN‑α secretion, pDC were exposed to different concentrations of HNSCC relevant cytokines such as IL‑6, IL‑8 and IL‑10. In accordance to former experiments we found that HNSCC micro milieu severely depresses up to 75% of IFN‑α secretion capacity of pDCs, if the stimulating Class A CpG 2216 is added to the culture. Preincubation of HNSCC supernatant leads to unrestorable reduction of IFN‑α secretion in pDC and can not be restored by CpG 2216. Incubation of pDCs with single cytokines relevant for cancer progression within the HNSCC micro milieu show that IL‑6 or IL‑8 have no influence on the IFN‑α secretion in pDCs, whereas IL‑10 massively impairs the secretion in a dose dependent manner. This effect can be potentiated by synergistic incubation with IL‑6 and can be abrogated by blocking antibodies to the IL‑10 receptor. Interestingly, incubation with IL‑10 is not the only factor that impairs the IFN‑α secretion, as incubation with the whole HNSCC supernatant is even more effective in reducing the secretion, implying that additional factors play a role. We conclude that restoration of HNSCC induced TH2 bias could be improved by the inhibition of immune cell cytokine receptors in addition to immunostimulating approaches with CpG motifs.

Platelets (PLT) are the second most abundant cell type in human blood and exert various immune-regulatory functions under both physiological and pathological conditions. In fact, immune cell regulation via platelets has been demonstrated in several studies within the past decade. However, the exact mechanisms behind T cell regulation remain poorly understood. We questioned whether the formation of aggregates of platelets and T cells has an impact on T-cell functions. In the present study, we stimulated PBMC cultures with anti-CD3 and anti-CD28 mABs and cultured them at a PLT: PBMC ratio of 1:1 or 100:1. After 24, 48, and 72 h, PD-1, PD-L1 expression, and proliferation were analyzed on T cells using flow cytometry. Cytokine production was measured in PHA stimulated CD4 cells after 6 h. We found a significant platelet-mediated decrease in PD-1 and PD-L1 expression, proliferation, as well as IFN-γ and TNF-α production. Perturbations also at least partially remained after spatial separation of PLTs from PBMCs in Transwell-assays. T cell-platelet aggregates showed similar levels of activation markers, proliferation, and secreted cytokines as their non-complexed counterparts. Results indicate a platelet mediated regulation of T cells via direct and indirect contact, but only mediocre effects of the complex formation itself.

Survivin (BIRC5) is an acknowledged cancer therapy-resistance factor and overexpressed in head and neck squamous cell carcinomas (HNSCC). Driven by its nuclear export signal (NES), Survivin shuttles between the nucleus and the cytoplasm, and is detectable in both cellular compartments in tumor biopsies. Although predominantly nuclear Survivin is considered a favorable prognostic disease marker for HNSCC patients, the underlying molecular mechanisms are not resolved. Hence, we performed immunohistochemical and mutational analyses using laser capture microdissection on HNSCC biopsies from patients displaying high levels of nuclear Survivin. We found somatic BIRC5 mutations, c.278T>C (p.Phe93Ser), c.292C>T (p.Leu98Phe), and c.288A>G (silent), in tumor cells, but not in corresponding normal tissues. Comprehensive functional characterization of the Survivin mutants by ectopic expression and microinjection experiments revealed that p.Phe93Ser, but not p.Leu98Phe inactivated Survivin's NES, resulted in a predominantly nuclear protein, and attenuated Survivin's dual cytoprotective activity against chemoradiation-induced apoptosis. Notably, in xenotransplantation studies, HNSCC cells containing the p.Phe93Ser mutation responded significantly better to cisplatin-based chemotherapy. Collectively, our results underline the disease relevance of Survivin's nucleocytoplasmic transport, and provide first evidence that genetic inactivation of Survivin's NES may account for predominantly nuclear Survivin and increased therapy response in cancer patients.