No description available.

Host innate and adaptive immune responses must be tightly regulated by an intricate balance between positive and negative signals to ensure their appropriate onset and termination while fighting pathogens and avoiding autoimmunity; persistent pathogens may usurp these regulatory machineries to dampen host immune responses for their persistence in vivo. Here, we demonstrate that miR146a is up‐regulated in monocytes from hepatitis C virus (HCV )‐infected individuals compared to control subjects. Interestingly, miR146a expression in monocytes without HCV infection increased, whereas its level in monocytes with HCV infection decreased, following Toll‐like receptor (TLR ) stimulation. This miR146a induction by HCV infection and differential response to TLR stimulation were recapitulated in vitro in monocytes co‐cultured with hepatocytes with or without HCV infection. Importantly, inhibition of miR146a in monocytes from HCV ‐infected patients led to a decrease in IL ‐23, IL ‐10 and TGF ‐β expressions through the induction of suppressor of cytokine signalling 1 (SOCS 1) and the inhibition of signal transducer and activator transcription 3 (STAT 3), and this subsequently resulted in a decrease in regulatory T cells (Tregs) accumulated during HCV infection. These results suggest that miR146a may regulate SOCS 1/STAT 3 and cytokine signalling in monocytes, directing T‐cell differentiation and balancing immune clearance and immune injury during chronic viral infection.

Atherosclerosis is an inflammatory disease in which an accumulation of fatty acids and cholesterol occurs to form a plaque in small and large arteries. Monocyte polarization to classic M1 macrophages or alternative M2 macrophages is an important area of research that can determine the severity of disease progression. BMP-7 is a key growth factor responsible for directing differentiation of mesenchymal stem cells into brown fat cells, suggesting a role of BMP-7 in cellular plasticity; however, its role in monocyte polarization is yet to be revealed. In the current study, we hypothesize that monocyte treatment with BMP-7 will significantly result in increased polarization of monocytes into M2 macrophages and increased expression of anti-inflammatory cytokines. To that effect, we have established a stress induced cell culture system with monocytes (THP-1 cells) and apoptotic conditioned medium (ACM), simulating injury, to understand the effects of BMP-7 on M2 macrophage polarization from monocytes. Our data demonstrates that the BMP type 2 receptor (BMPR2) is found on monocytes and its activation is significantly (p

Myeloid cells of the innate immune system have been strongly implicated in the pathogenesis of neurodegenerative diseases, including Alzheimer’s disease (AD) and Parkinson’s disease (PD). Similarly, several lines of evidence call on the adaptive immune system as a critical driver of disease, particularly in PD. The immune dynamics in both of these diseases are complex, and span across not only the innate and adaptive immune systems, but also across the periphery local action in the central nervous system (CNS). This thesis aims to address critical gaps in our knowledge regarding molecular and functional alterations of immune cells in AD and PD. We apply tools including single nucleus RNA – and ATAC – sequencing as well as protein – level and functional studies to advance our understanding of molecular pathways involved in the innate and adaptive immune dysfunction in these diseases, including both immune cells in the CNS as well as in the periphery. Chapter 1 provides an overview of the evidence implicating myeloid cell dysfunction in AD and PD, including microglia as well as peripheral myeloid cells such as monocytes. It also describes the features of immune dysregulation in both diseases, and evidence implicating the adaptive immune system in PD. Chapter 2 aims to address our currently limited understanding of microglial molecular phenotypes and diversity in PD, by characterizing microglial transcriptomic and chromatin signatures in disease. We demonstrate microglial subpopulation-specific effects, including the focal depletion of a microglial population in the substantia nigra in PD, which open novel avenues for targeted neuroimmune interventions in PD. Chapter 3 aims to identify interactions regulating the infiltration and retention of peripheral immune cells into the CNS in PD; a process which is implicated in the progression of this disease, but the mechanisms of which are not fully understood. We characterized transcriptomic signatures of infiltrating lymphocytes and blood brain barrier cells, and found increased T cell infiltration in PD as well as fibroblast and endothelial populations associated with disease. We further identified transcriptional shifts suggestive of a proinflammatory and profibrotic milieu in disease, in which chemokines and extracellular matrix elements produced by fibroblasts may influence T cell trafficking and retention in the substantia nigra in PD. Chapter 4 aims to address the gap in our knowledge of how myeloid dysfunction in the periphery contributes to AD. While genetics implicate all myeloid cells in AD and PD, contributions of peripheral myeloid cells, such as monocytes, have been largely overlooked in place of microglia, which are resident in the CNS. We evaluate the convergence of the AD genetic risk loci on functional outcomes in monocytes, in the context of Aβ as an immune stimulus. We identified functional convergence of the CD33 and SPI1 AD risk variants in the context of Aβ stress, including reduced phagocytosis and loss of surface TREM2 expression, demonstrating an interaction between genetics and environment to reduce myeloid cell fitness. Finally, Chapter 5 concludes with a summary of key findings from this work, and discusses future directions for modulating innate and adaptive immune populations, both in the CNS and in the periphery, as therapeutic approaches for these neurodegenerative diseases.

Psoriasis is an immune mediated inflammatory disease which affects 2-3% of the world’s population. Over the last decade, psoriasis has been acknowledged as an independent risk factor for atherosclerosis. The precise mechanism or mechanisms of the heightened risk is widely speculated. Endothelial cells and macrophages are central players in the immunopathological development of both diseases. Interleukin-36 cytokines (IL-36) have been heavily implicated in psoriasis immunopathology. Significant upregulation of epidermal IL-36 is a recognised characteristic of psoriatic skin inflammation. IL-36 induces inflammatory responses in dendritic cells, fibroblasts and epithelial cells. While vascular alterations are a hallmark of psoriatic lesions and dermal endothelial cells are well known to play a critical role in dermal inflammation, the effects of IL-36 on endothelial cells have not been defined. We report that endothelial cells including dermal microvascular cells express a functionally active IL-36 receptor. Adhesion molecules VCAM-1 and ICAM-1 are upregulated following IL-36γ stimulation, and this is reversed in the presence of the endogenous IL-36 receptor antagonist. IL-36γ-stimulated endothelial cells secrete the proinflammatory chemokines IL-8, CCL2 and CCL20. Chemotaxis assays showed increased migration of T-cells following IL-36γ stimulation of endothelial cells. Both resident and infiltrating inflammatory myeloid cells contribute to the immunopathology of psoriasis by promoting the IL-23/IL-17 axis. We show that IL-36γ induces the production of psoriasis-associated cytokines from macrophages (IL-23, TNFα) and that this response is enhanced in macrophages from psoriasis patients. This effect is specific for IL-36γ and could not be mimicked by other IL-1 family cytokines such as IL-1α. Furthermore, IL-36γ stimulated macrophages potently activated endothelial cells as illustrated by ICAM-1(CD54) upregulation, and led to increased adherence of monocytes, effects that were markedly more pronounced for psoriatic macrophages. Interestingly, regardless of stimulus, monocytes isolated from psoriasis patients showed increased adherence to both the stimulated and unstimulated endothelium when compared to monocytes from healthy individuals. Collectively, these findings add to the growing evidence for IL-36γ having roles in psoriatic responses, by enhancing endothelium directed leukocyte infiltration into the skin and strengthening the IL-23/IL-17 pathway. Our findings also point to a cellular response which could potentially support cardiovascular comorbidities in psoriasis. / University of Bradford and the Centre for Skin Sciences

No description available.

No description available.

No description available.

No description available.

No description available.