Dr Tom Nightingale

Profile

Research

Group members

Dr Sammy El-Mansi; Dr Tom Mitchell; Dr Paul Imbert

Summary 

Research in my lab centres on the cell biology of endothelial cells during injury and inflammation.

Currently two projects are running in the laboratory:

1. Trafficking of endothelial tight junction proteins during inflammation
Leukocyte recruitment from the blood vascular to infected tissues is a crucial part of the normal inflammatory response and allows clearance of pathogens from the affected area. However, in some situations inappropriate and excessive recruitment of leukocytes can result in chronically inflamed tissues. The control of this process is therefore central to a normal resolution of an inflammatory situation.
The blood vascular endothelium plays a key part in this process as a number of endothelial cell surface receptors such as P- and E-selectin, CD31 and the Junctional Adhesion Molecules (JAMs) have important roles in the recruitment and transmigration of leukocytes through blood-vessel walls. Some of these adhesion receptors such as Jam-C are known to undergo intracellular trafficking and are found on intracellular vesicles and non-junctional plasma membrane following certain stimuli. My research centres on the mechanisms and machinery required for this intracellular trafficking and the subsequent impact on transmigration of leukocytes through the endothelial cell layer.

2. An investigation into novel regulatory mechanisms for Von Willebrand factor secretion from endothelial cells
The response to vascular injury or infection is fast; this minimises loss of blood and spread of pathogens. As such, endothelial cells harbour specialised rod-shaped storage organelles (WPB) that contain multiple pre-made pro-inflammatory and pro-haemostatic proteins. Within minutes of endothelial cell stimulation WPB are exocytosed and release their stored content into the vasculature thus starting the processes of both haemostasis and leukocyte recruitment. The most important haemostatic component of WPB is the glycoprotein VWF that comprises 90% of stored protein. Upon exocytosis these tubules are unfurled by the shear force present in the blood vasculature to produce millimetre-long protein strings revealing multiple binding sites for platelets. Failure to secrete properly processed VWF either due to mutation of the protein itself or due to defects in cellular machinery associated with WPB formation result in bleeding (Von Willebrands disease). Conversely, a failure to appropriately remove VWF from the blood stream due to an inactivity or absence of the shear dependent metalloprotease ADAMSTS13, results in thrombotic thrombocytopenic purpura, a syndrome that is typified by multiple microvascular occlusions. These two syndromes additionally serve to highlight the importance of VWF in cardiovascular disease and stroke. Animal models and patients with VWF disease exhibit a decreased incidence of atherosclerosis. Conversely patients with elevated levels of VWF have an increased risk of major cardiac events and stroke.

We are investigating novel means to regulate VWF secretion that are controlled by an actomyosin ring. By understanding this mechanism we hope, in the long term, to develop novel strategies for limiting cardiovascular disease and stroke.

Key Publications

Full list of publications

1. Rolas L, Stein M, Barkaway A, Reglero-Real N, Sciacca E, Yaseen M, Wang H, Vasquez-Martinez L, Golding M, Blacksell I, Giblin M, Jaworska E, Bishop C, Voisin MB, Gaston-Massuet C, Fossati-Jimack L, Pitzalis C, Cooper D, Nightingale TD, Lopez-Otin C, Lewis M, Nourshargh S. Senescent endothelial cells promote pathogenic neutrophil trafficking in inflamed tissues EMBO Journal 2024 (in press)
2. El-Mansi S, Mitchell TP, Mobayen G, McKinnon TAJ, Miklavc P, Frick M, Nightingale TD. (2024) Myosin-1C augments endothelial secretion of von Willebrand factor by linking contractile actomyosin machinery to the plasma membrane. Blood Advances. 2024 Apr 26:bloodadvances.2024012590. doi: 10.1182/bloodadvances.2024012590. Online ahead of print.
3. Rolas L, Stein M, Barkaway A, Reglero-Real N, Sciacca E, Vazquez-Martinez L, Golding M, Blacksell IA, Giblin MJ, Jaworsk E, Bishop CL, Voisin M, Gaston-Massuet G, Fossati-Jimack L, Pitzalis C, Cooper D, Nightingale TD, Lopez-Otin C, Lewis M, Nourshargh S. (2023) Endothelial progerin expression promotes dysregulated neutrophil trafficking and neutrophil-dependent microvascular leakage in acute inflammation. Nature Comms. Under revision.
4. Bosseboeuf E, Chikh A, Chaker AB, Mitchell TP, Vignaraja D, Rajendrakumar R, Khambata RS, Nightingale TD, Mason JC, Randi AM, Ahluwalia A, Raimondi C. (2023) Neuropilin-1 prevents endothelial activation and interacts with TGFBR2 and VE-cadherin to promote adherens junction stability. Sci. Signalling. May 23;16(786): eabo4863.
5. El-Mansi S, Robinson CL, Kostelnik KB, McCormack JJ, Mitchell TP, Lobato-Marquéz D, Rajeeve V, Cutillas PR, Cutler DF, Mostowy S, Nightingale TD. (2023) Proximity proteomics identifies septins and PAK2 as decisive regulators of actomyosin-mediated expulsion of von Willebrand factor. Blood. Feb 23;141(8): 930-944
   
   Subject of Blood commentary and images from the paper appear as the front cover
   
   
6. Carpintero-Fernandez P, Borghesan M, Eleftheriadou O, Pan-Castillo B, Fafian J, Mitchell TP, Yuste A, Ogrunc M, Nightingale TD, Mayan M, and O'Loghlen A. (2022) Genome wide CRISPR/Cas9 screen identifies the coagulation factor IX (F9) as a regulator of senescence. Cell Death and Disease. Feb 19;13(2):163.
7. Reglero-Real N, Pérez-Gutiérrez L, Yoshimura A, Rolas L, Garrido-Mesa J, Barkaway A, Pickworth C, Saleeb RS, Gonzalez-Nuñez M, Austin-Williams SN, Cooper D, Vázquez-Martínez L, Fu T, De Rossi G, Golding M, Voisin MB, Boulanger CM, Kubota Y, Muller WA, Tooze SA, Nightingale TD, Collinson L, Perretti M, Aksoy E, Nourshargh S. (2021) Autophagy modulates endothelial junctions to restrain neutrophil diapedesis during inflammation. Immunity. Sep 14;54(9):1989-2004.e9.
8. El-Mansi S, Nightingale TD. (2021) Emerging mechanisms to modulate VWF release from endothelial cells. Int. J. Biochem. Cell Biol. Feb; 131:105900
9. Kostelnik KB, Barker A, Schultz C, Rajeeve V, White IJ, Aurrand-Lions M, Nourshargh S, Cutillas P, Nightingale TD. (2019) Dynamic trafficking and turnover of Jam-C is essential for endothelial cell migration. PLOS Biology. Dec 2;17(12):e3000554
10. Del Arroyo AG, Hadjihambi A, Sanchez J, Turovsky E, Kasymov V, Cain D, Nightingale TD, Lambden S, Grant SGN, Gourine AV, Ackland GL. (2019) NMDA receptor modulation of glutamate release in activated neutrophils. EBioMedicine, Sep:47:457-469
11. Nightingale TD*, McCormack JJ, Grimes W, Robinson C, Lopes Da Silva M, White IJ, Vaughan A, Cramer LP, Cutler DF. (2018) Tuning the endothelial response: Differential Release of exocytic cargoes from Weibel Palade Bodies. J.Thromb. Haemostasis, Sept; 16(9): p1873–1886. (* and corresponding)
12. Stevenson NL, White IJ, McCormack JJ, Robinson C, Cutler DF. Nightingale TD. (2017) Clathrin-mediated post-fusion membrane retrieval influences the exocytic mode of endothelial Weibel-Palade bodies. J. Cell Sci. Aug; 1;130(15) p2591-2605.

Collaborators

Internal

• Prof Sussan Nourshargh
• Dr James Whiteford
• Dr Mathieu-Benoit Voisin
• Dr Susana Godinho
• Dr Claudio Raimondi
• Dr Stephanie Kermorgant
• Prof Pedro Cutillas

External

• Prof Serge Mostowy (LSMTH)
• Prof Daniel Cutler (UCL)
• Dr Michel Aurrand-Lions (CRCM)
• Dr Isabelle Salles-Crawley (Imperial)
• Dr Jim Crawley (Imperial)
• Dr Ana O’Loghlen (CISC)

Teaching

• Module lead for BMD175-research skills for pharmacologists
• Academic lead for practical sessions BMD164-chromosomes and gene function
• Academic advisor for Pharmacology and Innovative Therapeutics students
• Supervisor for final year projects for Pharmacology and Innovative Therapeutics students
• PBL tutor for 1st and 2nd year medical students-cardiorespiratory, metabolism, locomotor and HSPH
• Ssc2a tutor for medical students

Disclosures

No disclosures.