Frank Kaiser

TRPV1 Deletion Enhances Local Inflammation and Accelerates the Onset of Systemic Inflammatory Response Syndrome

The transient receptor potential vanilloid 1 (TRPV1) is primarily localized to sensory nerve fibers and is associated with the stimulation of pain and inflammation. TRPV1 knockout (TRPV1KO) mice show enhanced LPS-induced sepsis compared with wild type (WT). This implies that TRPV1 may have a key modulatory role in increasing the beneficial and reducing the harmful components in sepsis. We investigated immune and inflammatory mechanisms in a cecal ligation and puncture (CLP) model of sepsis over 24 h. CLP TRPV1KO mice exhibited significant hypothermia, hypotension, and organ dysfunction compared with CLP WT mice. Analysis of the inflammatory responses at the site of initial infection (peritoneal cavity) revealed that CLP TRPV1KO mice exhibited: 1) decreased mononuclear cell integrity associated with apoptosis, 2) decreased macrophage tachykinin NK1-dependent phagocytosis, 3) substantially decreased levels of nitrite (indicative of NO) and reactive oxygen species, 4) increased cytokine levels, and 5) decreased bacteria clearance when compared with CLP WT mice. Therefore, TRPV1 deletion is associated with impaired macrophage-associated defense mechanisms. Thus, TRPV1 acts to protect against the damaging impact of sepsis and may influence the transition from local to a systemic inflammatory state.

Increased percentages of regulatory T cells are associated with inflammatory and neuroendocrine responses to acute psychological stress and poorer health status in older men and women

RationaleThe percentage of regulatory T cells (TRegs)—a subtype of T lymphocyte that suppresses the immune response—appears to be reduced in a number of stress-related diseases. The role of the TReg in stress-disease pathways has not yet been investigated.ObjectivesThe aim of the study was to investigate the association between biological responsivity to acute psychosocial stress and the percentage of TRegs in healthy older adults. The secondary purpose was to measure the associations between TReg percentage and psychological and physical well-being in the participants.MethodsSalivary cortisol and plasma interleukin (IL)-6 samples were obtained from 121 healthy older men and women from the Whitehall II cohort following acute psychophysiological stress testing. Three years later at a follow-up visit, we measured TReg percentages and psychological and physical well-being were recorded using the Short Form 36 Health Survey and the Center for Epidemiologic Studies Depression Scale.ResultsBlunted cortisol responses (p = 0.004) and elevated IL-6 responses (p = 0.027) to acute psychophysiological stress were associated with greater TReg percentage independently of age, sex, BMI, smoking status, employment grade, time of testing, and baseline measures of cortisol and IL-6, respectively. Percentage of TRegs was associated cross-sectionally with lower physical (p = 0.043) and mental health status (p = 0.008), and higher levels of depressive symptoms (p = 0.002), independently of covariates.ConclusionsIncreased levels of TRegs may act as a defence against increased inflammation and may be a pre-indication for chronically stressed individuals on the cusp of clinical illness.

Do reciprocal interactions between cell stress proteins and cytokines create a new intra-/extra-cellular signalling nexus?

Cytokine biology began in the 1950s, and by 1988, a large number of cytokines, with a myriad of biological actions, had been discovered. In 1988, the basis of the protein chaperoning function of the heat shock, or cell stress, proteins was identified, and it was assumed that this was their major activity. However, since this time, evidence has accumulated to show that cell stress proteins are secreted by cells and can stimulate cellular cytokine synthesis with the generation of pro- and/or anti-inflammatory cytokine networks. Cell stress can also control cytokine synthesis, and cytokines are able to induce, or even inhibit, the synthesis of selected cell stress proteins and may also promote their release. How cell stress proteins control the formation of cytokines is not understood and how cytokines control cell stress protein synthesis depends on the cellular compartment experiencing stress, with cytoplasmic heat shock factor 1 (HSF1) having a variety of actions on cytokine gene transcription. The endoplasmic reticulum unfolded protein response also exhibits a complex set of behaviours in terms of control of cytokine synthesis. In addition, individual intracellular cell stress proteins, such as Hsp27 and Hsp90, have major roles in controlling cellular responses to cytokines and in controlling cytokine synthesis in response to exogenous factors. While still confusing, the literature supports the hypothesis that cell stress proteins and cytokines may generate complex intra- and extra-cellular networks, which function in the control of cells to external and internal stressors and suggests the cell stress response as a key parameter in cytokine network generation and, as a consequence, in control of immunity.

Bacterial modulators of bone remodeling in the periodontal pocket

The signaling network involved in the pathogenesis of periodontal disease is not yet fully understood. This review aims to describe possible mechanisms through which the bacterial modulators may be linked directly or indirectly to the process of alveolar bone loss in periodontitis. From the late 1970s to present, new paradigm shifts have been developed regarding our understanding of pathological bone remodeling in periodontal disease. Upcoming evidence suggests that in periodontal disease the local immune response is exacerbated and involves the existence of signaling pathways that have been shown to modulate bone-cell function leading to alveolar bone loss. Those complex signaling pathways have been observed not only between bacteria but also between bacteria and the gingival surface of the host. More specifically, it has been shown that bacteria, through their secretion molecules, may interact indirectly and directly with immune-type cells of the host, resulting in the production of osteolytic agents that enhance bone resorption. Further research is required to provide a clear understanding of the role of these molecules in the pathogenesis of periodontal disease, and the availability of new technologies, such as next-generation sequencing and metagenomic analysis, may be useful tools in achieving this.

Secreted and Circulating Cell Stress Proteins in the Periodontal Diseases

The periodontal disease are the major source of human inflammatory pathology and so understanding the molecular and cellular pathology of periodontitis, and its response to treatment, is vital and secreted biomarkers may be useful. One key group of biomarkers are secreted cell stress proteins – now recognised to be potent intercellular signalling molecules. Periodontitis is not an infectious disease, but is driven by oral bacteria and so both bacterial and host cell stress proteins could be potential disease biomarkers. Both bacterial and human cell stress proteins have signalling actions on human leukocytes which could promote and/or inhibit periodontitis. Bacterial cell stress proteins have not been looked for in the circulation but there are antibodies to HSP60 and HSP90 in the blood of periodontal patients. So far little is known about circulating host cell stress proteins, but one treatment study reveals that patients have lower circulating levels of HSP10 and BiP, both anti-inflammatory molecules, than healthy controls, with successful treatment resulting in both proteins reaching normal levels, suggesting these proteins are natural anti-inflammatory signals in periodontitis. Another anti-inflammatory protein, HSP27, has, in unpublished studies, been shown to have diagnostic potential. These findings argue for much more detailed analysis of circulating cell stress proteins in the periodontal diseases.