Group leader: Isabelle Couillin
Our team studies danger signals, sensors and signaling pathways involved in lung inflammation in conditions such as Acute Respiratory Distress Syndrome (ARDS), pulmonary fibrosis and emphysema.
According to the World Health Organization, Chronic Obstructive Pulmonary Disease (COPD) is the third cause of death in the world. Repeated exposure to cigarette smoke is the leading cause of chronic lung inflammation and pulmonary emphysema characterized by irreversible damage of alveolar walls. Idiopathic Pulmonary Fibrosis (IPF), the most severe interstitial lung disease, is a devastating condition characterized by deregulation of tissue repair processes subsequent to lung tissue damage. Unbalanced repair results in lung scarring leading to a gradual loss of respiratory function. IPF triggers remain largely unknown, however this pathology often develops in smokers and former smokers. IPF and COPD are irreversible diseases and current treatments display very limited efficacy. The immunological events leading to these pathologies are not well understood.
Our team’s main objective is to decipher the physiopathological mechanisms of these diseases. Our research aims to identify endogenous molecules (danger signals released following lung tissue damage), their sensors as well as the signaling pathways activated during the establishment of innate and adaptive immune responses.We employ experimental models of pulmonary pathologies such as mouse exposure to cigarette smoke or other pollutants, as well as the administration into the respiratory tract of bleomycin to induce fibrosis, or of proteases to induce pulmonary emphysema. We identified uric acid and ATP as danger signals activating the NLRP3 inflammasome, leading to the maturation and secretion of pro-inflammatory interleukin (IL-) 1β, essential cytokine in fibrotic processes. We are currently studying the emerging functions of canonical (NLRP3, NLRP6) and non-canonical inflammasomes, related to the influence of the gut and lung microbiota on lung inflammation. We are investigating the role of self-nucleic acids as activators of other intra-cytosolic receptors such as cGAS-STING and its connection with type I and III interferons signaling pathways. We are also interested in the functions of B cell activating factor (BAFF) at the interface between innate and adaptive immunity.
A better understanding of the pathogenesis could favor the identification and validation of certain ligands or receptors as therapeutic targets, which can serve as a basis for screening tests to select molecules of pharmacological interest.
Results from recent publications :
2021 - Identification of the protective role of the STING DNA sensor in pulmonary fibrosis
STING deficiency leads to exacerbated fibrosis independently of type I interferon (IFN) signaling.
WT, Sting-/- and type I IFN receptor (Ifnar1-/-) deficient mice were treated with saline (NaCl) or the fibrosis inducing agent (bleomycin, BLM 3 mg/kg intranasaly) and the lungs were collected after 14 days. Histological lung sections stained with Red Sirius/Fast Green, which marks the collagen fibers in purple. The red and blue rectangles depict magnification and the black arrows collagen deposition.
2020 - B-Cell Activating Factor (BAFF) protein secretion by neutrophils plays an important role in lung inflammation following acute exposure to cigarette smoke
Acute exposure to cigarette smoke (CS) induces the production of BAFF by neutrophils recruited into the alveolar space and BAFF participates in inflammation.
Wild type (WT) or BAFF-deficient (BAFF-/-) mice were exposed to ambient air (AIR) or to cigarette smoke (CS) three times a day for four days and sacrificed 16 hours after last exhibition. (A) Immunofluorescence imaging showing cell nuclei (DAPI, blue) and BAFF (green) from bronchoalveolar lavage (BAL) cells of WT mice exposed or not to CS. BAFF labeling is localized within polylobed cells (neutrophils). (B) Quantification of fluorescence intensity. (C) ELISA assay showing BAFF levels in bone marrow neutrophil supernatants after stimulation with medium (Medium) or cigarette smoke extract (CSE) (D). Decreased neutrophils number in the BAL of CS-exposed BAFF-/- as compared to WT mice.
Mots clés: BPCO, Fibrose, Asthme, Inflammasome, Microbiote, IL-33, BAFF, IL-17, IL-22, IFN, NLRP3, NLRP6, STING, AhR.