Studies on Macrophage Migration in Pathological Contexts

Macrophages play key roles following nerve injury releasing cytokines and chemokines thought to be involved in the development and maintenance of neuropathic pain. ATP is a transporter of chemical energy, but can also act as an extracellular signalling molecule that signals through purinergic receptors. ATP, probably released from damaged neurons, can promote the migration of macrophages and microglia to the site of injury, and can be responsible for the onset of neuropathic pain. Purinergic signalling via ATP and other nucleotides is now well established and increasing evidence suggests that ATP could play important roles in pathophysiology. The neuroprotective neurotrophin brain derived neurotrophic factor (BDNF) inhibited ATP-induced invasion of macrophages though an extracellular matrix. The well-characterised Sigma-1 Receptor chaperone, previously implicated in BDNF function, was shown to be an important overall regulator of macrophage invasion, and to be potentially implicated in BDNF suppression of ATP-induced invasion. BDNF may thus have a neuroprotective role to inhibit further macrophage recruitment to the site of injury. Matrix metalloproteinases (MMPs) are capable of remodelling the extracellular matrix and the activation of inflammatory mediators. Exploration of MMP responses to extracellular ATP stimulation in a macrophage cell line revealed that MMPs -8, -12, and-13 as well as TIMP-2 steady state mRNA levels were significantly up-regulated ATP, ATP can alter matrix remodelling. Macrophage recruitment is a significant player in atherosclerosis and may be modulated by Apolipoprotein E genotype. N3-polyunsaturated fatty acids (obtained from dietary fish oils) have been implicated in cardiovascular protection. Using a high fat diet model the effects of dietary fish oil supplementation and Apolipoprotein E subtype were explored in ex vivo primary macrophages. Unexpectedly, a fish oil supplemented diet led increased macrophage migration speed and reduced TIMP-2 mRNA levels, suggesting that fish oil supplements play complex roles in atherosclerotic-related scenarios.

Name dc:type.qualificationname

phd

Level dc:type.qualificationlevel

doctoral

Grantor dc:publisher.institution

University of East Anglia

Year dc:date.issued

2014

Author dc:creator

• Yates, Matthew

Language dc:language

en