As key inflammation regulators, neutrophils are up there with all the other immune cells. An essential role that Véronique Witko-Sarsat has been helping to define for the past thirty years. Her research, which has not always been straightforward, has recently been awarded the International Association of Inflammation Societies’ Woman in Science prize.
After receiving the International Association of Inflammation Societies’ Woman in Science prize, Véronique Witko-Sarsat, leader of the Neutrophils and vasculitis team at Cochin Institute in Paris, is understandably delighted. « Without being militant, I am convinced that women need visibility, and that equality is compatible with scientific excellence, she emphasizes. And of course this award also marks the recognition of the crucial role played by neutrophils in inflammation! » A dual tribute to the career of this free spirit who is passionate about science and whose international reputation is firmly established.
« Neutrophilophiles »
It was in 1990 that, after obtaining her diploma in biology from the prestigious Conservatoire des arts et métiers (Cnam), she began a PhD at the Inserm Immunology and Nephrology Unit at Necker Hospital in Paris headed by Jean-François Bach. There she found what was to form the foundations of her life as a researcher: strong ties between researchers and doctors, and above all an immediate intellectual bond with nephrologist and emeritus researcher Béatrice Descamps-Latscha, who became her mentor. « It was thanks to her that I discovered the neutrophil. She also gave me great freedom – synonymous with creativity – and immediately encouraged me to present my research worldwide, » she emphasizes. Back then, « for most scientists, a neutrophil was simply a cell that during infection would destroy bacteria by producing oxidants to break down the tissues and would then die very quickly. It was not even worthy of being considered an immune cell! Only a few visionaries were interested in this marginal cell produced by our bodies in numbers ranging up to a mere 100 billion per day, » says the researcher, with irony.
Following her beginnings in Paris, in 1992 she seized the opportunity to join Carl Nathan’s laboratory at Cornell University in New York. « For neutrophils it was the laboratory of excellence whose publications I would read, she recalls. And this was where the seed planted by Descamps-Latscha really germinated, since I was able to join the international neutrophil community which has supported me throughout my career. » Following her return to the Inserm laboratory in 1994, she brought down her first dogma: neutrophils are not just antibacterials. They are also immune modulators! And in cystic fibrosis, neutrophils have abnormalities that make them supply oxidants, which maintain harmful inflammation in patients. Between obtaining her dissertation in 1995 and her Inserm position in 1999, Witko-Sarsat focused on her research subject, initiated in the US, which was to decipher the mysterious role of proteinase 3 (PR3), a target of the anti-neutrophil autoantibodies involved in vasculitis – particularly Wegener’s disease. In this disease, her team, together with the Department of Internal Medicine at Cochin Hospital headed by Luc Mouthon, showed that the PR3 located not inside the neutrophils but on the surface of their membrane, misleads the macrophages that mistakenly activate the immune system. A long series of discoveries through which therapeutic benefits could already be glimpsed…
Towards new anti-inflammatories?
The vagaries of science, and no doubt Witko-Sarsat’s own open-mindedness, led the team to focus on proliferating cell nuclear antigen (PCNA), a maestro of DNA replication which had long been considered to be restricted to the cell nucleus. « But we observed it in the cytoplasm of neutrophils! explains Witko-Sarsat. At first, I thought it was a mistake in our experiments but as it intrigued me, I tried to understand. » The outcome being that in 2010 she called into question another dogma: that PCNA is not just found in the cell nucleus. Present in the cytoplasm, it controls programmed neutrophil death, and in leukemia cells, it promotes their resistance to treatment. The team had therefore put its finger on a mechanism that could enable the development of anti-inflammatories that are more targeted than corticosteroids, because they directly attack the neutrophil – the orchestral conductor of inflammation.
In keeping with Descamps-Latscha’s philosophy, the researcher set about sharing her findings with other « neutrophilophiles » worldwide, whether original or recently converted. Today, « neutrophils have earned their stripes: the French Society of Immunology even has a Neutrophil Club, and our team was accredited by the Foundation for Medical Research (FRM) in 2020. So new avenues are opening up for us! » she enthuses. Her next challenges? Reprogram neutrophils to control inflammation not just in vasculitis, but also in cancer, cystic fibrosis and even COVID-19… even if it means continuing to move the lines. Passion is non-negotiable! « Even in my personal life, my work and neutrophils have never been negotiable, » acknowledges the researcher who also thrives on the creativity of modern art, and salsa, « a dance where it is impossible not to smile and share, » she emphasizes; two other passions… that are equally non-negotiable!
Véronique Witko-Sarsat is the leader of the Neutrophils and vasculitis team at the Cochin Institute (unit 1016 Inserm/CNRS/Université Paris-Cité).