Yoshinari Nakatsuka^1,2, 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

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.