{"database":"biostudies-literature","file_versions":[],"scores":null,"additional":{"submitter":["Trujillo G"],"funding":["Boehringer-Ingelheim","Yale ILD Center of Excellence","NCATS NIH HHS","NHLBI NIH HHS","National Heart, Lung, and Blood Institute","NHGRI NIH HHS","Pulmonary Fibrosis Foundation"],"pagination":["91-102"],"full_dataset_link":["https://www.ebi.ac.uk/biostudies/studies/S-EPMC11755360"],"repository":["biostudies-literature"],"omics_type":["Unknown"],"volume":["211(1)"],"pubmed_abstract":["<b>Rationale:</b> Idiopathic pulmonary fibrosis (IPF) is a fatal lung disease for which current treatment options only slow clinical progression. Previously, we identified a subset of patients with IPF with an accelerated disease course associated with fibroblast expression of Toll-like receptor 9 (TLR9) mediated by interactions with its ligand mitochondrial DNA. <b>Objectives:</b> We aimed to show that TLR9 activation induces fibroproliferative responses that are abrogated by its antagonism by using two commercially available indirect inhibitors and a proprietary, selective direct small-molecule inhibitor. <b>Methods:</b> We employed two independent cohorts of patients with IPF, multiple <i>in vitro</i> fibroblast cell culture platforms, an <i>in vivo</i> mouse model, and an <i>ex vivo</i> human precision-cut lung slices system to investigate the clinical and biologic significance of TLR9 in this disease. <b>Measurements and Main Results:</b> In two independent IPF cohorts, plasma mitochondrial DNA activates TLR9 in a manner associated with the expression of monocyte chemoattractant protein 1, IL-6, tumor necrosis factor-α, and IFN-γ-inducible protein 10 and worsened transplant-free survival. Our cell culture platform showed that TLR9 mediates fibroblast activation via transforming growth factor-β1 and stiff substrates and that its antagonism, particularly direct inhibition, ameliorates this process, including production of these TLR9-associated pharmacodynamic endpoints. We further demonstrated that direct TLR9 inhibition mitigates these fibroproliferative responses in our <i>in vivo</i> and <i>ex vivo</i> models of pulmonary fibrosis. <b>Conclusions:</b> In this novel study, we found that direct TLR9 inhibition mitigates fibroproliferative responses in preclinical models of pulmonary fibrosis. Our work demonstrates the therapeutic potential of direct TLR9 antagonism in IPF and related fibrotic lung diseases."],"journal":["American journal of respiratory and critical care medicine"],"pubmed_title":["Toll-like Receptor 9 Inhibition Mitigates Fibroproliferative Responses in Translational Models of Pulmonary Fibrosis."],"pmcid":["PMC11755360"],"funding_grant_id":["U54 HG008540","K08HL151970-01","U01 HL145567","U01 HL122626","R01 HL152677","UL1 TR001863","U54HG008540","K08 HL151970","U01HL145567","U01HL122626","UG3TR002445","R01 HL127349","R01 HL163984","R01HL127349","UG3 TR002445"],"pubmed_authors":["Trujillo G","Khoury J","Pivarnik T","Yu S","McGovern J","Antin-Ozerkis DE","Ahangari F","Regueiro-Ren A","Hu B","Sun Y","Ryu C","Ishikawa G","Al Jumaily K","Woo S","Lee CJ","Sauler M","Peng XY","Liu C","Sun H","Walia A","Fiorini V","Herzog EL","Kaminski N"],"additional_accession":[]},"is_claimable":false,"name":"Toll-like Receptor 9 Inhibition Mitigates Fibroproliferative Responses in Translational Models of Pulmonary Fibrosis.","description":"<b>Rationale:</b> Idiopathic pulmonary fibrosis (IPF) is a fatal lung disease for which current treatment options only slow clinical progression. Previously, we identified a subset of patients with IPF with an accelerated disease course associated with fibroblast expression of Toll-like receptor 9 (TLR9) mediated by interactions with its ligand mitochondrial DNA. <b>Objectives:</b> We aimed to show that TLR9 activation induces fibroproliferative responses that are abrogated by its antagonism by using two commercially available indirect inhibitors and a proprietary, selective direct small-molecule inhibitor. <b>Methods:</b> We employed two independent cohorts of patients with IPF, multiple <i>in vitro</i> fibroblast cell culture platforms, an <i>in vivo</i> mouse model, and an <i>ex vivo</i> human precision-cut lung slices system to investigate the clinical and biologic significance of TLR9 in this disease. <b>Measurements and Main Results:</b> In two independent IPF cohorts, plasma mitochondrial DNA activates TLR9 in a manner associated with the expression of monocyte chemoattractant protein 1, IL-6, tumor necrosis factor-α, and IFN-γ-inducible protein 10 and worsened transplant-free survival. Our cell culture platform showed that TLR9 mediates fibroblast activation via transforming growth factor-β1 and stiff substrates and that its antagonism, particularly direct inhibition, ameliorates this process, including production of these TLR9-associated pharmacodynamic endpoints. We further demonstrated that direct TLR9 inhibition mitigates these fibroproliferative responses in our <i>in vivo</i> and <i>ex vivo</i> models of pulmonary fibrosis. <b>Conclusions:</b> In this novel study, we found that direct TLR9 inhibition mitigates fibroproliferative responses in preclinical models of pulmonary fibrosis. Our work demonstrates the therapeutic potential of direct TLR9 antagonism in IPF and related fibrotic lung diseases.","dates":{"release":"2025-01-01T00:00:00Z","publication":"2025 Jan","modification":"2026-06-13T04:54:40.614Z","creation":"2026-06-13T03:08:47.297Z"},"accession":"S-EPMC11755360","cross_references":{"pubmed":["39189851"],"doi":["10.1164/rccm.202401-0065OC","10.1164/rccm.202401-0065oc"]}}