AUTHOR=Goto Shinya , Konnai Satoru , Hirano Yuki , Kohara Junko , Okagawa Tomohiro , Maekawa Naoya , Sajiki Yamato , Watari Kei , Minato Erina , Kobayashi Atsuhi , Gondaira Satoshi , Higuchi Hidetoshi , Koiwa Masateru , Tajima Motoshi , Taguchi Eiji , Uemura Ryoko , Yamada Shinji , Kaneko Mika K. , Kato Yukinari , Yamamoto Keiichi , Toda Mikihiro , Suzuki Yasuhiko , Murata Shiro , Ohashi Kazuhiko 

TITLE=Upregulation of PD-L1 Expression by Prostaglandin E2 and the Enhancement of IFN-γ by Anti-PD-L1 Antibody Combined With a COX-2 Inhibitor in Mycoplasma bovis Infection

JOURNAL=Frontiers in Veterinary Science

VOLUME=7

YEAR=2020

URL=https://www.frontiersin.org/journals/veterinary-science/articles/10.3389/fvets.2020.00012

DOI=10.3389/fvets.2020.00012

ISSN=2297-1769

ABSTRACT=<p>Bovine mycoplasmosis caused by <italic>Mycoplasma bovis</italic> results in pneumonia and mastitis in cattle. We previously demonstrated that the programmed death 1 (PD-1)/PD-ligand 1 (PD-L1) pathway is involved in immune dysfunction during <italic>M. bovis</italic> infection and that prostaglandin E<sub>2</sub> (PGE<sub>2</sub>) suppressed immune responses and upregulated PD-L1 expression in Johne's disease, a bacterial infection in cattle. In this study, we investigated the role of PGE<sub>2</sub> in immune dysfunction and the relationship between PGE<sub>2</sub> and the PD-1/PD-L1 pathway in <italic>M. bovis</italic> infection. <italic>In vitro</italic> stimulation with <italic>M. bovis</italic> upregulated the expressions of PGE<sub>2</sub> and PD-L1 presumably via Toll-like receptor 2 in bovine peripheral blood mononuclear cells (PBMCs). PGE<sub>2</sub> levels of peripheral blood in infected cattle were significantly increased compared with those in uninfected cattle. Remarkably, plasma PGE<sub>2</sub> levels were positively correlated with the proportions of PD-L1<sup>+</sup> monocytes in <italic>M. bovis</italic>-infected cattle. Additionally, plasma PGE<sub>2</sub> production in infected cattle was negatively correlated with <italic>M. bovis</italic>-specific interferon (IFN)-γ production from PBMCs. These results suggest that PGE<sub>2</sub> could be one of the inducers of PD-L1 expression and could be involved in immunosuppression during <italic>M. bovis</italic> infection. <italic>In vitro</italic> blockade assays using anti-bovine PD-L1 antibody and a cyclooxygenase 2 inhibitor significantly upregulated the <italic>M. bovis</italic>-specific IFN-γ response. Our study findings might contribute to the development of novel therapeutic strategies for bovine mycoplasmosis that target PGE<sub>2</sub> and the PD-1/PD-L1 pathway.</p>