6IMS researchers have developed a spontaneous mouse model of idiopathic pulmonary fibrosis – opening the door to identifying novel endogenous targets for treatment.Researchers are racing against time to find effective treatments for patients with idiopathic pulmonary fibrosis (IPF), a chronic disease that causes scarring of the lungs and ultimately respiratory failure and death within just two to five years of diagnosis. A major missing link in this pur-suit could be an animal model that accurately represents the disease in patients.“The majority of fibrosis research uses the bleomycin-induced model,” explained Kazuyo Moro, Team Leader of the Laboratory for Innate Immune Systems at IMS. In this model, injection of the antibiotic bleomycin damages epithelial cells to induce fibrosis. “The damage to cells is equivalent to and useful for studying smoking or asbestos-related fibrosis, but most patients don’t live in these condi-tions, and still fibrosis occurs,” Moro added.The bleomycin-induced model is also transient, which contrasts to the chronic and progressive nature of IPF in humans. Instead, an animal model that develops fibrosis spontaneously and irreversibly with age could reveal never-before-studied endogenous pathways in IPF.To Moro’s surprise, her team had developed such a model without knowing it. In their previous research into immune cells called group 2 innate lymphoid cells (ILC2), the team had generated double knockout mice lacking the Rag2 gene to eliminate the adaptive immune system and a gene that encodes an interferon gamma receptor (Ifngr1). One year after completing that study, they discovered that the lungs of these mice turned white with age due to in-creased collagen production, a hallmark of IPF.Without prior background in IPF, Moro and her team collaborated with clinical researchers from Tokai Univer-sity and Kanagawa Cardiovascular and Respiratory Center to explore how fibrosis arises in this model and the types of cells involved.In their paper published in Nature Communications, the researchers showed that the model mice were born with normal lung function before spontaneously develop-ing inflammation followed by fibrosis by around 20 weeks of age. Thanks to the progressive nature of these changes, the team was able to study IPF in three phases, the intact, inflammatory, and fibrotic phases – a feat that is impos-sible with the bleomycin-induced model and could be key to identifying the endogenous players causing IPF.In fact, one cell type that was dramatically increased in the inflammatory and fibrotic phases was ILC2. Large numbers of ILC2 were found in fibrotic areas of the lungs, along with high levels the cytokine IL-33.As IL-33 is a known to activate ILC2, the team searched for its cellular origins. In addition to epithelial cells, an already well-known source, the researchers were surprised to discover that fibroblasts, the main producers of collagen in fibrosis, also make IL-33. Co-culture experiments con-firmed that activating ILC2 with IL-33 directly induced fibroblasts to produce collagen.“We found that fibroblasts themselves produce IL-33, which can activate ILC2,” Moro noted. “Those activated ILC2 can then again stimulate fibroblasts to produce more IL-33,” creating a feed-forward loop that could explain how IPF progresses in the absence of external stimulation.Armed with some understanding of which endogenous players are driving IPF, the team is now conducting in-depth studies into the mechanisms by which these factors induce and exacerbate IPF in the hopes of providing pa-tients with more effective treatment solutions.Figure: Double knockout mice lacking a gene encoding an interferon gamma receptor (Ifngr1) and adaptive immunity due to elimination of the Rag2 gene form a novel model of idiopathic pul-monary fibrosis (IPF)Sections of lung tissue from the mouse model of IPF were labeled with Masson’s trichrome stain to reveal collagen fibers in blue. While collagen production was low in young mice, levels increased in the absence of external stimulation as the mice aged, with fibrosis evident by around 20 weeks of age.Original paper:Otaki N, Motomura Y, Terooatea T, Thomas Kelly S, Mochizuki M, Takeno N, Koyasu S, Tamamitsu M, Sugihara F, Kikuta J, Kitamura H, Shiraishi Y, Miyanohara J, Nagano Y, Saita Y, Ogura T, Asano K, Minoda A, Moro K. Activation of ILC2s through constitutive IFNγ signaling reduction leads to spontaneous pulmonary fibrosis. Nat Commun 14, 8120 (2023)Kazuyo MoroProbing idiopathic pulmonary fibrosis from within
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