CD200R Regulates Neutrophil Function in Health and Disease

UoM administered thesis: Phd

  • Authors:
  • Mark Fife

Abstract

Regulation of neutrophil migration and function is important in health and disease, as loss of control can cause pathology. Regulation occurs at multiple stages including their release from the bone marrow, migration into tissues, activation and life span. This thesis investigates the role of CD200R in regulating neutrophil function during health and disease. Interaction of CD200R with its ligand CD200 produces a unidirectional signal via CD200R, which is restricted to myeloid cells. CD200 has a short cytoplasmic tail that does not couple to any intracellular signalling cascade. CD200R signalling recruits DOK2, which in turn recruits RasGAP that inhibits Ras and ultimately phosphorylation ERK and PI3 kinase. It therefore inhibits innate inflammation. Such regulation by CD200R has been extensively documented in macrophages, but not neutrophils. The hypothesis tested in this thesis is that CD200R expression on neutrophils is necessary to control their activity in health and disease either by affecting their a) egress from the bone marrow, b) maturity in the periphery, and c) activity, including phagocytosis. Using wild-type (WT) and CD200R knock-out mice and an agonistic CD200R antibody, this thesis dissects the functional implications of CD200R signalling in acute airway inflammation. The results show that CD200R plays a critical role in regulating neutrophil number, maturity and function in health and disease. CD200R ligation therefore provides an alternative strategy for the treatment of diseases associated with excess neutrophilia.

Details

Original languageEnglish
Awarding Institution
Supervisors/Advisors
Award date1 Aug 2017