Interrogation and modulation of the myeloid aspect of the inflammatory immune response in spinal cord injury

Montgomery, Jennifer (2013) Interrogation and modulation of the myeloid aspect of the inflammatory immune response in spinal cord injury. PhD thesis, University of Glasgow.

Abstract

Spinal cord injury (SCI) affects approximately 40,000 people in the UK; the most common type of SCI is a contusion injury and the majority of these cases are male and aged between 16 and 30 years old. The initial physical trauma to the spinal cord during injury leads to substantial damage and loss of neurones. After the primary traumatic insult has occurred a sequence of events is initiated that sets off a cascade of biochemical, cellular and inflammatory events that are massively destructive and continue for weeks to months after the initial SCI. This phenomenon is known as “secondary death” and leads to an increase in the size of the damaged area. Infiltrating monocytes and monocyte-derived macrophage have been implicated as a crucial component in the perpetration of secondary death.

It was demonstrated in this thesis that staphylococcus protein A (SpA), when in complex with IgG forms homogeneous small immune complexes (SIC) that can polarize macrophages in vitro to an anti-inflammatory phenotype, resulting in increased production of the immune-suppressive cytokine IL-10 and reduced ability to produce the pro-inflammatory cytokine IL-12. SIC treatment of IFNγ-primed macrophages in conjunction with LPS also induces a down-regulation of MHC II surface expression; however, the macrophages still exhibit normal levels of co-stimulatory molecule CD86 compared to a classically-activated macrophage.
In an in vivo setting it was demonstrated that SpA binds to monocytes and preferentially to the “inflammatory” Ly6Chi monocyte sub-set. The binding of SpA to this monocyte population induced the maturation of the Ly6Chi “inflammatory” monocyte into Ly6Clow “anti-inflammatory” monocytes within the steady state and in the sterile inflammatory setting of SCI. In the inflammatory environment of the damaged spinal cord, SpA treatment induced a higher percentage of Ly6Clow monocytes to produce the immune-modulatory cytokine IL-10 compared to the control treated group. These observations indicate when SpA and IgG form SIC they interact with macrophages and monocytes in vitro or in vivo polarizing them to an anti-inflammatory phenotype.

In conclusion, it has been shown in this thesis that SIC has the potential to be used as a method of polarizing monocytes and macrophages to an anti-inflammatory phenotype, which in turn has the potential to modify the overt inflammatory response that is responsible for the death of neurons days to weeks after the initial injury and is responsible for reduced functional recovery in SCI patients.

• Item Type: Thesis (PhD)
• Qualification Level: Doctoral
• Keywords: Spinal cord injury, inflammation, immune modulation, macrophage, monocyte
• Subjects: Q Science > QR Microbiology > QR180 Immunology
• Colleges/Schools: College of Medical Veterinary and Life Sciences > School of Infection & Immunity > Immunology & Infection
• Supervisor's Name: Goodyear, Dr. Carl
• Date of Award: 2013
• Depositing User: Miss Jennifer Montgomery
• Unique ID: glathesis:2013-4820
• Copyright: Copyright of this thesis is held by the author.
• Date Deposited: 31 Jan 2014 14:05
• Last Modified: 31 Jan 2014 14:14
• URI: https://theses.gla.ac.uk/id/eprint/4820