Use this URL to cite or link to this record in EThOS: https://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.799063
Title: Investigating the expression and function of IL-16 in central nervous system under normal and inflammatory conditions
Author: Hridi, Shehla Unaiza
ISNI:       0000 0004 8509 5730
Awarding Body: University of Strathclyde
Current Institution: University of Strathclyde
Date of Award: 2018
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Abstract:
Multiple Sclerosis (MS) is an inflammatory demyelinating disease of the central nervous system (CNS). MS pathophysiology is complex and CD4+ T cells are one of the key mediators involved in the disease initiation and progression. Interestingly CD4 is also the receptor for interleukin-16 (IL-16), a pro-inflammatory cytokine. Previous re-search has shown that IL-16 is involved in the development of several autoimmune diseases such as rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), Graves' disease (GD) and MS, but the exact role of IL-16 during MS initiation and progression remains unclear. Therefore, the aim of this study was to understand the role of IL-16 in CNS inflammation by: (i) examining the expression and distribution of IL-16 in the CNS and investigating whether expression levels correlate with the se-verity of neuroinflammation in experimental autoimmune encephalomyelitis (EAE), a murine model of MS; and (ii) by further determining the function of IL-16 in the CNS under normal physiological condition. We immunised C57BL/6j mice with myelin oligodendrocyte glycoprotein (MOG35-55) to induce EAE and utilised immunohistochemistry to study the expression of IL-16 and its receptor CD4 in the lymphoid and CNS tissues at different stages of EAE. While CD4 was expressed in lymphoid tissues of both EAE and control mice, CD4 expression in CNS tissues was only observed during EAE. For IL-16, its levels in the lymphoid organs and CNS tissues of EAE mice were significantly increased com-pared to tissues of naïve and PBS controls, as confirmed by the quantification of the percentage of IL-16+ cells in tissues. Surprisingly, soluble IL-16 produced by spleno-cytes was similar between groups of naïve, and PBS or MOG35-55 immunised mice, and there was no difference with or without MOG35-55 stimulation in the culture. To identify the cell source of IL-16 in the lymphoid and CNS tissues we next utilised double immunofluorescence staining and our data showed co-localisation of IL-16 with some immune cells during EAE, with CD11b+ cells (macrophages and microglia) expressing the highest percentage of IL-16 in both types of tissues. However, in CNS, IL-16 was also co-localised with CNS resident cells including neurons in both EAE and control mice and astrocytes only during EAE. However further study is required to fully understand the exact underlying action mechanisms of IL-16 in EAE. Following that we investigated the role of IL-16 in CNS function by examining whether IL-16 modulates neuronal excitability and synaptic activity in mouse primary hippo-campal cultures. We observed application of recombinant IL-16 (rIL-16) protein impaired sEPSC frequency and amplitude in a CD4-independent manner. We examined the mechanisms underlying these effects with rIL-16 reducing GluA1 S831 phosphorylation and inhibiting Na+ channel function. Taken together, our data suggest that IL-16 expression levels in both lymphoid organs and CNS tissues correlate with CNS inflammation, and CD11b+ cells are the main source of IL-16 in both tissues during CNS inflammation in our EAE disease model. Under normal physiological condition, IL-16 reduces neuronal excitability and synap-tic activity via multiple mechanisms and it is likely that its function is not solely dependent on the presence of CD4. Clearly IL-16 have a role both under normal and pathophysiological state but whether it is detrimental or beneficial is yet to be identified and requires further investigation to identify the exact role and potential of IL-16 in treatment of MS.
Supervisor: Jiang, Hui-Rong ; Bushell, Trevor Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID: uk.bl.ethos.799063  DOI:
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