Investigation of the role of WIP and WASP in regulating myeloid cells migration during mild hyperthermia

Abstract

Local mild hyperthermia stimulates the activity of immune cells including prompting leukocyte migration and trafficking, but the molecular mechanisms involved in this process are poorly understood. The Wiskott Aldrich Syndrome Protein (WASP) and the WASP interacting protein (WIP) work as a functional unit that plays a major role in assembly and disassembly of myeloid cell adhesions termed podosomes by binding both F-actin and other actin-related proteins. Besides, WIP can also regulate actin dynamics by modulating the lipid composition of the plasma membrane, as recently shown in neurons. In various organisms, the lipid composition and fluidity of the cell membrane work as a thermosensor that regulates the cellular response to changes in temperature. This study aimed to investigate whether WIP or WASP may regulate the migratory response to mild hyperthermia as in local inflammation or during a febrile event.

Results showed that mild hyperthermia (40°C) promoted random cell migration correlating with the assembly of more robust and dynamic podosomes with increased matrix degradation capability in a WASP and WIP-dependent manner. We observed that this response is dependent on the actin polymerising activity and the nuclear translocation of WASP.

Our data also indicate that increased membrane fluidity, like the one induced by hyperthermia, can trigger a migratory response in myeloid cells. Following hyperthermia, WIP delivers changes in monocytic cells membrane lipid composition to maintain fluidity homeostasis in the plasma membrane, particularly in podosomal areas at adhesion sites, triggering the increased invasive migratory capacity. The modulation of the lipid composition of the plasma membrane is mediated by the WIPdependent regulation of genes involved in lipid biosynthesis and rafts formation in response to hyperthermia. These genes include NSMAF, OSBPL5 and regulators of cholesterol biosynthesis. In response to hyperthermia, WIP also controls the upregulation of Heat Shock protein 90 (HSP90), a protein previously associated with podosome formation. This process is independent of WASP.

Taken together, our data show a role of both WIP and WASP in the increased migratory phenotype of myeloid cells in response to mild hyperthermia.

Date of Award	16 Apr 2020
Original language	English
Awarding Institution	University of Roehampton
Supervisor	Yolanda Calle (Supervisor) & Michal Letek Polberg (Supervisor)