Immune cells in the pulmonary fibrotic niche: friend or foe?
Department of Biological Sciences & Engineering: department Seminar
Venue: Online platform
Time: 10:30 AM
Date: 19 Jul 2023
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Meeting ID: 942 6178 7423
Passcode: 825497
Figure 1 The 3-cell circuit in the pulmonary fibrotic niche
Idiopathic pulmonary fibrosis (IPF) is a disease which is characterized by progressive scarring of the lung parenchyma which ultimately leads to respiratory failure. Our lab has recently shown by Single Cell RNA sequencing (Sc-RNA seq) analysis that macrophages are highly compartmentalized in bleomycin induced lung injury model of pulmonary fibrosis and a subcluster of these macrophages has a pro-fibrotic phenotype and anti- fibrotic phenotype.
In the first study1 using genetic mouse model, Sc-RNA seq and FACS, we could show that profibrotic monocyte derived macrophages (MoMacs) secrete Platelet derived growth factor A (Pdgfa) which in turn binds to its receptor, Pdgfra, highly expressed in the fibroblast compartment within the lungs. We also observed that Treg cells secrete the anti-inflammatory cytokine IL10 which in turn binds to its receptor, IL10Ra on MoMacs, thereby promoting Pdgfa secretion from this MoMacs after lung injury.
In another study2 using Precision Cut Lung Slice (PCLS) imaging in genetic mouse models, Sc-RNA Seq, and ex vivo models, we could show macrophages secrete ATP via its connexin hemichannels (Cx43) after bleomycin induced lung injury. The secreted ATP in turn binds to its purinergic receptor P2rx4, highly expressed in fibroblast, promoting Ca2+ within these cells and in turn fibrosis.
In contrast to the other studies, this study3 using Sc-RNA Seq analysis and generation of new Knockout (KO) mouse with CRISPR/Cas9, we could show anti-fibrotic macrophages secrete the Sphingosine 1-Phosphate Lyase(S1PL), an enzyme which irreversibly cleaves the profibrotic factor Sphingosine 1-Phosphate (S1P) which promotes pulmonary fibrosis. However, this secretion may not be enough to mount an anti-fibrotic effect, so we showed a proof-of-concept study whereby we delivered S1PL using gene therapy which led to better outcome of pulmonary fibrosis.
IPF is a disease which is characterized by accumulation of cellular senescence (CS). In the final study done at our biotech company, we could show when we reactivate the adaptive immune system, more specifically invariant natural killer T (iNKT) cells with our lead molecule, its leads to reduction of CS after lung injury and better outcome of pulmonary fibrosis.
Taken together, these four studies show us how we can target the immune compartment in the fibrotic niche which will help in developing therapeutics against IPF
- Bhattacharyya, A. et al. IL10 trains macrophage profibrotic function after lung injury. American Journal of Physiology-Lung Cellular and Molecular Physiology 322, L495– L502 (2022).
- Bhattacharyya, A. et al. Macrophage Cx43 Is Necessary for Fibroblast Cytosolic Calcium and Lung Fibrosis After Injury. Frontiers in Immunology 13, (2022).
- Bhattacharyya, A. et al. Adeno-associated virus mediated SGPL1 gene therapy as treatment for reducing inflammation during lung fibrosis. Mol. Ther. Nucleic Acids under review.
