File(s) not publicly available

Reason: Restricted by author. A copy can be supplied under Section 51(2) of the Australian Copyright Act 1968 by submitting a document delivery request through your library or by emailing document.delivery@monash.edu

Chemokine networks in neuroinflammation following focal traumatic brain injury

thesis
posted on 16.01.2017 by Semple, Bridgette Deanne
Traumatic brain injury (TBI) is a leading cause of death and disability worldwide. In addition to the primary insult, activation of secondary injury cascades such as inflammation contributes to ongoing neurodegeneration and long-term neurological deficits. Chemokines (chemotactic cytokines), which mediate the activation and migration of specific leukocyte subsets, have been detected at elevated levels in both head-injured patients and animal models of focal TBI, and are likely responsible for the characteristic infiltration of neutrophils and macrophages into the injured brain. However, the relative importance of chemokines and their receptors to neuroinflammation and neuropathology after TBI have not been elucidated. This thesis aimed to understand the contributions of two major chemokine networks to post-traumatic neuroinflammation and secondary tissue damage, by the use of gene-deficient mice subjected to a closed head injury model of focal TBI, and an in vitro model of astrocyte inflammation. We firstly examined the function of CXCR2, the principle chemokine receptor mediating neutrophil chemotaxis, by examining Cxcr2-/- mice after closed head injury. Deficiency of the Cxcr2 gene almost completely ablated neutrophil infiltration post-injury, despite the early upregulation of several CXC neutrophil-attracting chemokines in the lesioned cortex. Coincidently, a reduction in tissue damage, neuronal loss and cell death was noted in Cxcr2-/- mice compared to wild-type mice, particularly at 7 days post-injury, with heterozygotes showing intermediate responses. These findings demonstrate the importance of CXC chemokine signalling in the injured brain, and highlight the deleterious contribution of neutrophils to post-traumatic neurodegeneration. In the second study, mice deficient in the macrophage chemokine CCL2 were examined over four weeks after closed head injury. Ccl2-/- mice had an unexpectedly altered profile of cytokine production acutely post-injury (2-24 hours), however, this did not affect lesion volume or cell death within the first week. In contrast, by 2-4 weeks, a delayed reduction in tissue damage, macrophage accumulation and astrogliosis were observed in the injured cortex and ipsilateral thalamus of Ccl2-/- mice, corresponding to improved functional recovery compared to wild-type mice. These results confirm a non-redundant role for CCL2 in mediating macrophage recruitment into the injured brain, and implicate CCL2-responsive macrophages in the perpetuation of secondary brain damage. In the third study, we explored the potential immunomodulatory role of CCL2 in neuroinflammation in vitro. We found that primary astrocytes isolated from Ccl2-/- mice had an exacerbated cytokine response to the inflammatory stimuli lipopolysaccharide and interleukin (IL)-1β, corresponding to our findings in the mouse cortex post-injury. In line with this, treatment of astrocytes with recombinant CCL2 was able to inhibit IL-1β-mediated expression and production of IL-6. These findings indicate a previously unrecognised role of this chemokine in modulating acute inflammatory responses in the brain, distinct from its role in macrophage recruitment. Altogether, this thesis indicates the central, critical roles of CCL2 and CXCR2 signalling in leukocyte infiltration into the injured brain, and provides valuable insight into the contribution of neuroinflammation to post-traumatic degeneration. These studies have implications for the development of future therapeutic approaches aimed at targeting chemokine systems to improve outcomes for TBI patients.

History

Principal supervisor

M Cristina Morganti-Kossmann

Year of Award

2010

Department, School or Centre

Medicine

Campus location

Australia

Course

Doctor of Philosophy

Degree Type

DOCTORATE

Faculty

Faculty of Medicine Nursing and Health Sciences

Exports