Yanick CROW

Our research aims to understand innate immune homeostasis, type I interferon signalling, and the pathogenic consequences — at both the cellular and tissue level — of the inappropriate recognition of self-nucleic acids as foreign ligands.

Our contribution to this field of expertise began with the study of Aicardi–Goutières syndrome (AGS), a Mendelian autoinflammatory disorder characterised by severe neuroinflammation and excessive type I interferon signalling. Over the past 15 years, a larger group of diseases - similarly associated with chronically enhanced activation of the type I interferon system - has come to be designated as the type I interferonopathies, with our team playing a key role in defining the genetic basis and phenotypic spectrum of many of these disorders, now extending from neuroinflammation to pro-fibrotic lung inflammation.

Today, our research contributes to a better understanding of the mechanisms involved in the type I interferonopathies at every scale: genetic, cellular and tissue. Further, the study of these monogenic diseases has led us and others to explore the importance of the type I interferon pathway in the pathophysiology of certain non-Mendelian conditions, most notably systemic lupus erythematosus.

Our research is organised according to three main objectives:

1 – Gene identification

Our work leads to the regular discovery of new genes involved in type I interferon signalling and its regulation. Alongside this work, drawing on our expertise in clinical phenotyping, we also aim to define genotype-phenotype correlations, disease natural history, and factors explaining variable phenotypic expression and clinical penetrance, through genetic approaches (the search for additional protective or aggravating genetic factors) and transcriptomic approaches (allelic expression bias).

2 – Dissecting mechanism at the cellular level

The study of the type I interferonopathies enables us to dissect the intracellular mechanisms underlying self-derived nucleic acid-driven autoinflammation. Currently, we have a particular focus on nucleic acids derived from mitochondria and from retroelements in different cell types and organs. In addition, we are interested in the interplay between distinct intracellular innate immune pathways, exploring reciprocal influences as a basis to explain the complexity of autoinflammatory disease, with the aim of designing tailored therapeutic combinations.

3 – Development of innovative cellular and tissue models

This line of research aims to understand the chronic inflammation and organ damage seen in the type I interferonopathies, particularly in the brain and lung, using models derived from induced pluripotent stem cells (iPSCs).

To address the cellular basis of neuroinflammation, we model the crosstalk between the main cell types present in the brain, with the purpose of identifying the relevant sources and targets of type I interferons, as well as the neurotoxic mediators at play in type I interferon-mediated neuroinflammation.

To decipher the cellular basis of the pro-fibrotic lung inflammation observed in certain type I interferonopathies, we are developing lung-on-a-chip models to identify the cells involved both in the initiation and the maintenance of chronic lung inflammation, and in the pro-fibrotic transition.

Understanding neuroinflammation and lung inflammation in these rare Mendelian diseases sheds light on mechanisms relevant to disorders that are common in the general population, from neurodegeneration to idiopathic pulmonary fibrosis.

The translational dimension of our research

Novel therapeutic approaches are urgently needed for the type I interferonopathies, given their severity, associated morbidity and refractoriness to conventional treatments. In this respect, work from our group and others indicates that it is possible to use specific ‘anti-interferon’ approaches to block inflammation driven by nucleic acids and type I interferons (see, for example: Frémond et al. J Allergy Clin Immunol 2016;138:1752–1755; Kothur et al. Neurology 2018;90:289–291; Briand et al. Ann Rheum Dis 2019;78:431–433; Rice et al. N Engl J Med 2018;379:2275–2277; Frémond et al. J Clin Immunol 2023;43:1436–1447). By identifying potential novel biomarkers and targeted therapies, we hope to further advance precision medicine approaches to discrete type I interferonopathies, while also providing insights relevant to more common inflammatory diseases.

Team organisation:
Marie-Louise Frémond: STING-mediated inflammation and its consequences on tissue
Alice Lepelley: Mitochondrial inflammation and neuroinflammation