Lung fibroblasts produce IL-33 in response to stimulation with retinoblastoma-binding protein 9 via production of prostaglandin E2. (3rd June 2020)

• Record Type: Journal Article
• Authors: Adachi, Takumi; Yasuda, Koubun; Muto, Taichiro; Serada, Satoshi; Yoshimoto, Tomohiro; Ishii, Ken J; Kuroda, Etsushi; Araki, Kimi; Ohmuraya, Masaki; Naka, Tetsuji; Nakanishi, Kenji
• Is Part Of: International immunology. Volume 32:Number 10(2020)
• Page Start: 637
• Page End: 652
• Publication Date: 2020-06-03
• Subjects: damage-associated molecular patterns -- cyclooxygenase-2 -- group 2 innate lymphoid cells -- Loeffler's syndrome -- Strongyloides venezuelensis; Immunology -- Periodicals; 616.079
• DOI: 10.1093/intimm/dxaa031
• Languages: English
• ISSNs: 0953-8178

Abstract

Abstract: Intestinal nematode infection induces pulmonary eosinophilia via IL-33, although the mechanism of pulmonary IL-33 induction remains unclear. Because nematode migration damages lungs, we speculated that lung-derived damage-associated molecular patterns (DAMPs) possess an IL-33-inducing activity (IL33ia). Indeed, intra-nasal administration of a lung extract induced IL-33 production in lungs. Additionally, lung extracts increased Il33 mRNA expression in primary lung fibroblasts. Proteomic analysis identified retinoblastoma-binding protein 9 (RBBP9) as a major DAMP with IL33ia. RBBP9 was originally discovered as a protein that provides cells with resistance to the growth inhibitory effect of transforming growth factor (TGF)-β1. Here, we found that stimulation by RBBP9 induced primary fibroblasts to produce prostaglandin E2 (PGE2 ) that, in turn, induced fibroblasts to produce IL-33. RBBP9-activated fibroblasts expressed mRNAs of cyclooxygenase-2 (COX-2) and PGE2 synthase-1 that convert arachidonic acid to PGE2 . Furthermore, they expressed PGE2 receptors E-prostanoid (EP) 2 and EP4. Thus, treatment with a COX-2 inhibitor or EP2 and/or EP4 receptor antagonists inhibited RBBP9-induced IL-33 production. Nematode infection induced pulmonary Il33 mRNA expression, which was inhibited by the COX-2 inhibitor or EP2 and EP4 antagonists, suggesting that nematode infection induced pulmonary Il33 mRNA via PGE2 . RBBP9 was expressed constitutively in the lung in the steady state, which did not increase after nematode infection. Finally, we found that Rbbp9 -deficient mice had a significantly diminished capacity to increase pulmonary Il33 mRNA expression following nematode infection. Thus, the PGE2 -EP2/EP4 pathway activated by RBBP9 released from damaged lungs is important for pulmonary IL-33 production in nematode-infected animals. Abstract : Nematode-damaged lungs induce IL-33 production via RBBP9 and PGE2