Exploring the bidirectional interface between stress and innate immunity: a focus on glucocorticoid and TLR4-MyD88 signalling

Abstract

Multiple bidirectional interactions between stress neuroendocrine and innate immunity have been identified in previous research, but the extent of these interactions remain unresolved. This thesis thus aimed to explore the bidirectional interface between stress and innate immunity, by focusing on glucocorticoid and TLR4- MyD88 signalling. The research was undertaken in a series of 3 studies. Study 1 investigated the impact of baseline TLR4-MyD88 signalling on the neuroendocrine and behavioural responses to acute stress. Through examining stress responses in mice lacking Tlr4 or Myd88, this study found an intrinsic influence of TLR4-MyD88 signalling on both neuroendocrine and behavioural responses. Aadaptations to the feedforward and feedback pathways of glucocorticoid signalling were also identified. Studies 2 and 3 explored the effects of glucocorticoid signalling on innate immune function in immunocompetent cells. In these 2 studies, BV2 microglia-like cells, RAW264.7 macrophage-like cells and adult primary microglia were utilised. Study 2 demonstrated a biphasic innate immune response to glucocorticoids, where low concentrations of corticosterone pre-exposure primed, while a high stress-like concentration of corticosterone suppressed TLR4-NF-κB-IL-1β responses. Using pharmacological antagonists, it was further revealed that the priming effect on IL-1β was mediated by mineralocorticoid receptor (MR) signalling, while immunosuppressive actions were mediated by glucocorticoid receptor (GR) signalling. Study 3 further assessed glucocorticoid actions on non-cytokine innate immune responses via measurements of cell motility, cell death and danger-associated molecular pattern (DAMP)-related protein release. Here, a low concentration of corticosterone increased ATP-induced BV2 cell motility. Signalling via GR, a stress-like concentration of Corticosterone and Dexamethasone caused an increase in cytotoxicity and HMGB1 DAMP protein release. Collectively, the findings in this thesis provide support for multiple intrinsic connections between the stress neuroendocrine and TLR4 signalling pathway, both in vivo and in vitro. Further mechanistic insights such as GR and MR signalling were revealed, and the implications of this work to health and disease were also discussed.