PEPITEM, a regulator of leukocyte trafficking in ageing

Hopkin, Sophie Jo (2023). PEPITEM, a regulator of leukocyte trafficking in ageing. University of Birmingham. Ph.D.

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Abstract

With the continued advancement of modern medicine, the global ageing population is expanding. Although lifespan has been dramatically extended since the mid-1800s, preserving an individual’s healthspan remains a challenge. Chronic inflammatory diseases are increasing within the older population and is in part driven by the age-related changes to the immune system (e.g. inflammageing, immunesenescence). Growing evidence suggests that ageing is associated with dysregulated leukocyte trafficking processes, which may contribute to the development of age-related inflammatory diseases. The PEPtide Inhibitor of TransEndothelial Migration (PEPITEM) is an immunoregulatory peptide that suppresses T-cell transmigration, but its ability to control T-cell trafficking in aged systems is currently unknown.

In this thesis we explored age-related and sex-specific changes to leukocyte trafficking patterns in vivo and in vitro. We found that ageing was associated with increased numbers of leukocytes within the peritoneal cavity under steady state, particularly in female mice, suggesting increased homeostatic leukocyte trafficking to this tissue. An increased inflammatory environment within the cavity and increased permeability of the peritoneal membrane vasculature likely supported increased leukocyte trafficking to this tissue in aged mice.

Using in vitro and in vivo models of acute inflammation, we next explored age-related changes to inflammatory leukocyte trafficking. We found that ageing did not affect peripheral blood lymphocyte (PBL) adhesion to nor migration across inflamed endothelial cells in vitro, however, changed the composition of migrating PBL. Using a model of zymosan-induced peritonitis, we found that aged mice, particularly female
mice, had an exacerbated inflammatory response to zymosan challenge where significantly more leukocytes were recruited to the peritoneal cavity. Following on from this, we demonstrated the ability of PEPITEM to control leukocyte trafficking in older mice and humans using these in vitro and in vivo models of inflammation. However, the PEPITEM pathway was evidently dysfunctional in older adults as adiponectin (initiator of the PEPITEM pathway) failed to control the transendothelial migration of PBL from older donors in vitro. We found that age-related changes to peripheral blood B-cells, including reduced expression of signalling components downstream of the adiponectin receptors (e.g. APPL1), led to reduced production of the PEPITEM parent protein, 14-3-3ζ, in response to adiponectin.

Thus, within this thesis, we report that age-related changes to leukocyte trafficking dynamics in vivo are sexually dimorphic. Using models of inflammation, we have demonstrated that PEPITEM can control the trafficking of leukocytes from older hosts. Finally, we have identified that the PEPITEM pathway is dysfunctional in older adults, which may contribute to the dysregulated leukocyte trafficking processes observed in ageing.

Type of Work:

Thesis (Doctorates > Ph.D.)

Award Type:

Doctorates > Ph.D.

Supervisor(s):