Neuroinflammation is an important contributor to the pathogenesis of many neurological diseases. A key component of the innate immune response in the central nervous system is the migration of neutrophils into the brain parenchyma, where they exacerbate neuronal injury and worsen clinical outcome. A greater understanding of the mechanisms underlying neutrophil influx into the brain may aid the development of novel therapeutic interventions for the variety of diseases to which neutrophils contribute, notably including stroke and epilepsy. In vitro evidence implicates the pro- inflammatory cytokine, interleukin-1α (IL-1α), derived from platelets as a key mediator of cerebrovascular inflammation and neutrophil migration across brain endothelial cells.The aim of the work in this thesis was to test if this mechanism is important in vivo.We investigated the contribution of platelets and IL-1 in a murine model of neutrophil migration into the peritoneal cavity in response to injection of lipopolysaccharide (LPS). Depletion of platelets abrogated the migration of neutrophils in response to LPS- induced peritonitis, indicating an important role for platelets in the process. Genetic knockout of IL-1 had no effect on neutrophil influx, demonstrating that migration in the peritoneum occurs independently of IL-1.The discovery that neutrophil migration in LPS-induced peritonitis was independent of IL-1 contrasted with the finding that platelet-derived IL-1 was a mediator of neutrophil influx across mouse brain endothelial cells in vitro. The question arose as to whether IL-1 was required as a mediator of neutrophil migration in extra-cerebral tissues. Hence, we tested the contribution of platelets and IL-1 in two further in vivo models of neutrophil migration: LPS injection into a subcutaneous air pouch, and acute lung injury induced by LPS inhalation. Platelet depletion significantly reduced neutrophil migration into the air pouch in response to LPS, yet had no effect in acute lung injury. This indicated that neutrophil migration into the air pouch was dependent on platelets, and that migration into the lungs was platelet-independent. LPS induced the same degree of neutrophil migration in wild-type and IL-1 knockout mice, demonstrating that IL-1 was not required for neutrophil migration in either model.To determine the contribution of platelets and IL-1 to neutrophil migration in response to cerebrovascular inflammation, we injected LPS into the mouse striatum. In this model, neutrophil influx to the brain parenchyma in response to LPS was reduced by depletion of circulating platelets, and inhibition of the platelet adhesion molecule, GpIb. Genetic knockout of IL-1α significantly reduced the number of invading neutrophils induced by LPS. These data confirmed that both platelets and IL-1α were important contributors to cerebral neutrophil migration in vivo. To determine whether platelets in systemic circulation may be the source of IL-1α, we treated mice with IL-1 receptor antagonist or anti-IL-1 antibodies to block systemic IL-1 action. Neither intervention affected cerebral neutrophil migration in response to LPS, suggesting that the IL-1α that mediates neutrophil migration may originate in the brain.Overall, these data demonstrate that IL-1α and platelets make an important contribution to neutrophil migration to the brain, yet independently of each other. Our data also suggest there may be specific mechanisms driving innate immune responses in vivo even in response to the same inflammatory stimulus.
| Identifer | oai:union.ndltd.org:bl.uk/oai:ethos.bl.uk:559358 |
| Date | January 2012 |
| Creators | Giles, James |
| Contributors | Allan, Stuart; Lawrence, Catherine |
| Publisher | University of Manchester |
| Source Sets | Ethos UK |
| Detected Language | English |
| Type | Electronic Thesis or Dissertation |
| Source | https://www.research.manchester.ac.uk/portal/en/theses/the-role-of-plateletderived-interleukin1-alpha-as-a-driver-of-neutrophil-migration-in-vivo(8097504b-42c5-40c3-a18c-419bf79ebfb8).html |
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