The role of GPR87 in Pulmonary Fibrosis

Khoury, J.; Ahangari, F.; Adams, T.; Justet, A.; Manning, E.; McDonough, J. E.; Barnthaler, T.; Anderson, S.; Nikola, F.; Beermann, M. L.; Gomez, J. L.; Kaminski, N.

doi:10.1101/2024.10.10.617569

bioRxiv · 10.1101/2024.10.10.617569

The role of GPR87 in Pulmonary Fibrosis

Khoury, J.·Ahangari, F.·Adams, T.·Justet, A.·Manning, E.·McDonough, J. E.·Barnthaler, T.·Anderson, S.·Nikola, F.·Beermann, M. L.·Gomez, J. L.·Kaminski, N.

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Abstract

RationaleG- protein coupled receptor 87 (GPR87), an alternative lysophosphatidic acid (LPA) receptor previously implicated in cancer, is highly expressed in basal and aberrant basaloid cells in idiopathic pulmonary fibrosis (IPF). We sought to determine whether signaling through GPR87 is important to the development of pulmonary fibrosis. MethodsReanalysis of bulk and single cell RNA sequencing dataset was performed to confirm the increased expression of GPR87 in pulmonary fibrosis. The role of GPR87 in fibrosis in-vivo was assessed using global GPR87 knockout (GPR87-/-) and wildtype mice in the bleomycin model of pulmonary fibrosis, in-vitro in induced pluripotent stem cells (iPSCs) derived airway basal cells (iBC) using GPR87 siRNAs, and ex-vivo in human precision cut slices using disease free tissues in the fibrotic cocktail model as well as IPF tissues treated with GPR87 siRNA. ResultsGPR87 is highly expressed in IPF lungs, and its expression correlates with disease severity. Furthermore, It is highly expressed in basal and aberrant basaloid cells. GPR87-/- mice are protected against bleomycin induced pulmonary fibrosis. GPR87 knockdown is protective against fibrosis development in normal PCLS treated with fibrotic cocktail and leads to fibrosis regression in IPF PCLS. In iBC, GPR87 knockdown leads to decreased expression of fibrosis related genes, proteins and microRNAs. GPR87 stimulation with LPA leads to the opposite results. The main downstream pathways are PI3K, mTOR, and TNF/NFkB; stimulation or inhibition of PI3K pathway mimics GPR87 stimulation or inhibition responses, respectively. ConclusionGPR87 is highly expressed in basal and aberrant basaloid cells in IPF lungs and seems to mediate profibrotic effects based on in-vivo, ex-vivo and in-vitro models of disease, suggesting that it should be studied as a potential epithelial specific therapeutic target in pulmonary fibrosis.

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Khoury, J., Ahangari, F., Adams, T., Justet, A., Manning, E., McDonough, J. E., Barnthaler, T., Anderson, S., Nikola, F., Beermann, M. L., Gomez, J. L., Kaminski, N.. 2024-10-11. The role of GPR87 in Pulmonary Fibrosis. https://doi.org/10.1101/2024.10.10.617569

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