Vermeren, Sonja

Amour, Augustin

Hansen, Carsten

Michael, Melina

Medical Research Council (MRC)

Roslin Inst, BBSRC Roslin Institute

GlaxoSmithKline (GSK)

2022-11-21T11:54:48Z

2022-11-21T11:54:48Z

2022-11-21

Neutrophils form part of the innate immune system, they are the most abundant circulating leukocytes in humans and play a crucial role in host defence and inflammation. Upon stimulation, neutrophils leave the blood stream and chemotax to sites of inflammation after which they employ a range of effectors functions to eliminate the threat. It is key that these functions are tightly controlled to ensure pathogen clearance and prevent a suboptimal neutrophil response, as is observed in immunosenescence, defined by the deterioration of the immune system with old age. However, it is also essential to avoid the inappropriate activation of the immune response which could lead to autoimmune diseases. Through a range of receptors, the activation of phosphoinositide 3-kinase (PI3K) signalling regulates many aspects of neutrophil biology. Phosphatidylinositol 3,4,5-trisphosphate (PIP3), the lipid second messenger product of PI3K is subjected to dephosphorylation by several 5’phosphatases, converting it into PI(3,4)P2, a lipid second messenger in its own right. The SHIP family 5’phosphatases include the well characterised leukocyte restricted SHIP1, and the ubiquitously expressed SHIP2. SHIP1-deficient neutrophils spread extensively on the substratum, and in response to chemoattractant stimulation fail to chemotax efficiently towards a chemoattractant. Here, SHIP2 is characterised using mice with catalytically inactive SHIP2, revealing an in vivo recruitment defect to sites of sterile inflammation. Isolated neutrophils from catalytically inactive SHIP2 mice were also identified to have chemotaxis, directionality, and polarisation defects in vitro. Several other effector functions were also tested including phagocytosis and swarming but portrayed a lack of any major defects. The effects of catalytically inactive SHIP2 are mechanistically explained by a subtle increase in PIP3 and an larger decrease in PI(3,4)P2. The effects of immunosenescence have been well documented in the adaptive immune system, however, its effects on in the innate immune system have yet to be robustly explored. Therefore, I studied the effects of neutrophil ageing on its effector functions and identified a defect in neutrophil swarming in the absence of defects in elastase release and the formation of reactive oxygen species This is congruent with results from other groups identifying a chemotaxis defect in neutrophils from older donors. In summary, my work identifies a non-redundant role for SHIP2 in neutrophil chemotaxis and trafficking, further enhancing our understanding of the PI3K signalling pathways in neutrophils. I also studied the phenotype of immunosenescent neutrophils, identifying a defect in neutrophil swarming.

https://hdl.handle.net/1842/39503

http://dx.doi.org/10.7488/era/2753

en

The University of Edinburgh

Michael, M., McCormick, B., Anderson, K. E., Karmakar, U., Vermeren, M., Schurmans, S., Amour, A., & Vermeren, S. (2021). The 5-Phosphatase SHIP2 Promotes Neutrophil Chemotaxis and Recruitment. Frontiers in immunology, 12, 671756.

Chu, J. Y., McCormick, B., Mazelyte, G., Michael, M., & Vermeren, S. (2019). HoxB8 neutrophils replicate Fcγ receptor and integrin-induced neutrophil signaling and functions. Journal of leukocyte biology, 105(1), 93–100.

Michael, M., & Vermeren, S. (2019). A neutrophil-centric view of chemotaxis. Essays in biochemistry, 63(5), 607–618.

neutrophils

chemoattractants

PI3K

PIP3 phosphatases

SHIP2

inflammation

neutrophil migration

effects of ageing

Effects of the PI3K pathway on neutrophil chemotaxis and swarming

Thesis or Dissertation

Doctoral

PhD Doctor of Philosophy