All transcripts were created with artificial intelligence software and modified with manual review by a third party. Although we make every effort to ensure accuracy with the manual review, some may contain computer-generated mistranslations resulting in inaccurate or nonsensical word combinations, or unintentional language. FASEB and the presenting speakers did not review the transcripts and are not responsible and will not be held liable for damages, financial or otherwise, that occur as a result of transcript inaccuracies.
Role of Lysophosphatidic Acid Signaling Via LPA3 in Developing Lung Fibrosis
Junken Aoki 1, Shun Nishikado 1, Shun Yaginuma 1, Kuniyuki Kano 1, Jumpei Omi 1,1 Graduate School of Pharmaceutical Sciences, University of Tokyo
Background and Aims: In addition to direct activation by pathogens and antigens, immune cell functions are further modulated by factors in their environment. Recent studies have revealed that lysophospholipids (LPL) derived from membrane glycerophospholipids, are such environmental factors. They are produced by the action of various phospholipases and modulate immune responses positively or negatively via GPCR-type receptors. These include lysophosphatidic acid (LPA), lysophosphatidylserine (LysoPS) and lysophosphatidylinositol (LPI). Among these lysophosphollipid GPCRs, GPCRs for LysoPS (LPS1, LPS2, LPS2L and LPS3) are almost exclusively expressed in immune cells, suggesting that LysoPS has immune-modulative roles.
Methods: To investigate the immunomodulatory potential of LysoPS, an antigen immunization model was applied to each LysoPS receptor KO mice. In addition, we applied the tumor-bearing and infection models to LPS1 (GPR34) KO mice to investigate the function of LPS1 signaling in cancer and infection immunity.
Results: Immunization of mice via foot pads with TNP-ovalbumin, a T-cell-dependent antigen, causes enlargement of the popliteal lymph node, the lymph node beneath the knee, and an increase in the number of immune cells including T, B lymphocytes, macrophages and dendritic cells. In LPS1 KO mice, the enlargement of popliteal lymph node was attenuated and the immune cells in the lymph node decrease in number. Conversely, administration of an LPS1-selective agonist further enhanced the popliteal lymph node hypertrophy and increased the number of various immune cells. In contrast, LPS2/LPS2L/LPS3 TKO and LPS2/LPS2L DKO mice showed marked lymph node enlargement and increased cell counts, especially of B cells, after immunization with TNP-ovalbumin.
Treatment of LPS1 KO mice with MC-38 colon cancer cells resulted in a marked increase in cancer tissue size. Conversely, LPS1 agonist administration decreased cancer tissue size. Similarly, the clearance of Streptococcus pneumoniae was found to be significantly reduced in LPS1 KO mice.
Conclusion: LysoPS was found to positively or negatively regulate immune responses, depending on the receptor types. LPS1 signaling, which positively regulates immunity, was found to enhance cancer and infectious disease immunity.
This study was supported partly by JSPS KAKENHI Grant Number 22H00438.
Speakers
Junken Aoki