Institute for Frontier Life and Medical Sciences, Kyoto University

Pulmonary Regnase-1 orchestrates the interplay of epithelium and adaptive immune systems to protect against pneumonia

Yoshinari Nakatsuka1,2, Alexis Vandenbon1, Takashi Mino1, Masanori Yoshinaga1, Takuya Uehata1, Xiaotong Cui1, Ayuko Sato3, Tohru Tsujimura3, Yutaka Suzuki4, Atsuyasu Sato2, Tomohiro Handa2, Kazuo Chin2, Teiji Sawa5, Toyohiro Hirai2, Osamu Takeuchi1

(1 Institute for Frontier Life and Medical Sciences Kyoto University. 2 Graduate School of Medicine, Kyoto University. 3 Department of Pathology, Hyogo College of Medicine. 4 Graduate School of Frontier Sciences, The University of Tokyo. 5 Department of Anesthesiology, Kyoto Prefectural University of Medicine)

“Pulmonary Regnase-1 orchestrates the interplay of epithelium and adaptive immune systems to protect against pneumonia”

Mucosal Immunology (Advance online publication)
DOI: 10.1038/s41385-018-0024-5
Springer Nature (PDF): https://rdcu.be/MyWp

Abstract

Inhaled pathogens including Pseudomonas aeruginosa initially encounter airway epithelial cells (AECs), which are poised to evoke cell-intrinsic innate defense, affecting second tier of hematopoietic cell-mediated immune reaction. However, it is largely unknown how pulmonary immune responses mediated by a variety of immune cells are coordinated. Here we show that Regnase-1, an endoribonuclease expressed in AECs and immune cells, plays an essential role in coordinating innate responses and adaptive immunity against P. aeruginosa infection. Intratracheal treatment of mice with heat-killed P. aeruginosa resulted in prolonged disappearance of Regnase-1 consistent with sustained expression of Regnase-1 target inflammatory genes, whereas the transcription factor NF-B was only transiently activated. AEC-specific deletion of Regnase-1 not only augmented innate defenses against P. aeruginosa but also enhanced secretion of Pseudomonas-specific IgA and Th17 accumulation in the lung, culminating in conferring significant resistance against P. aeruginosa re-infection in vivo. Although Regnase-1 directly controls distinct sets of genes in each of AECs and T cells, degradation of Regnase-1 in both cell types is beneficial for maximizing acquired immune responses. Collectively, these results demonstrate that Regnase-1 orchestrates AEC- and immune cell-mediated host defense against pulmonary bacterial infection.