Reprogramming of profibrotic macrophages for treatment of bleomycin‐induced pulmonary fibrosis
Abstract Fibrotic diseases cause organ failure that lead to ~45% of all deaths in the United States. Activated macrophages stimulate fibrosis by secreting cytokines that induce fibroblasts to synthesize collagen and extracellular matrix proteins. Although suppression of macrophage‐derived cytokine p...
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| Format: | Article |
| Language: | English |
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Springer Nature
2020-06-01
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| Series: | EMBO Molecular Medicine |
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| Online Access: | https://doi.org/10.15252/emmm.202012034 |
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| author | Fenghua Zhang Ehab A Ayaub Bingbing Wang Estela Puchulu‐Campanella Yen‐Hsing Li Suraj U Hettiarachchi Spencer D Lindeman Qian Luo Sasmita Rout Madduri Srinivasarao Abigail Cox Konstantin Tsoyi Cheryl Nickerson‐Nutter Ivan O Rosas Philip S Low |
| author_facet | Fenghua Zhang Ehab A Ayaub Bingbing Wang Estela Puchulu‐Campanella Yen‐Hsing Li Suraj U Hettiarachchi Spencer D Lindeman Qian Luo Sasmita Rout Madduri Srinivasarao Abigail Cox Konstantin Tsoyi Cheryl Nickerson‐Nutter Ivan O Rosas Philip S Low |
| author_sort | Fenghua Zhang |
| collection | DOAJ |
| description | Abstract Fibrotic diseases cause organ failure that lead to ~45% of all deaths in the United States. Activated macrophages stimulate fibrosis by secreting cytokines that induce fibroblasts to synthesize collagen and extracellular matrix proteins. Although suppression of macrophage‐derived cytokine production can halt progression of fibrosis, therapeutic agents that prevent release of these cytokines (e.g., TLR7 agonists) have proven too toxic to administer systemically. Based on the expression of folate receptor β solely on activated myeloid cells, we have created a folate‐targeted TLR7 agonist (FA‐TLR7‐54) that selectively accumulates in profibrotic macrophages and suppresses fibrosis‐inducing cytokine production. We demonstrate that FA‐TLR7‐54 reprograms M2‐like fibrosis‐inducing macrophages into fibrosis‐suppressing macrophages, resulting in dramatic declines in profibrotic cytokine release, hydroxyproline biosynthesis, and collagen deposition, with concomitant increases in alveolar airspaces. Although nontargeted TLR7‐54 is lethal at fibrosis‐suppressing doses, FA‐TLR7‐54 halts fibrosis without evidence of toxicity. Taken together, FA‐TLR7‐54 is shown to constitute a novel and potent approach for treating fibrosis without causing dose‐limiting systemic toxicities. |
| format | Article |
| id | doaj-art-6c2ab7c60e9040ec977bb024e8f6c67b |
| institution | Kabale University |
| issn | 1757-4676 1757-4684 |
| language | English |
| publishDate | 2020-06-01 |
| publisher | Springer Nature |
| record_format | Article |
| series | EMBO Molecular Medicine |
| spelling | doaj-art-6c2ab7c60e9040ec977bb024e8f6c67b2025-08-20T03:43:21ZengSpringer NatureEMBO Molecular Medicine1757-46761757-46842020-06-0112811510.15252/emmm.202012034Reprogramming of profibrotic macrophages for treatment of bleomycin‐induced pulmonary fibrosisFenghua Zhang0Ehab A Ayaub1Bingbing Wang2Estela Puchulu‐Campanella3Yen‐Hsing Li4Suraj U Hettiarachchi5Spencer D Lindeman6Qian Luo7Sasmita Rout8Madduri Srinivasarao9Abigail Cox10Konstantin Tsoyi11Cheryl Nickerson‐Nutter12Ivan O Rosas13Philip S Low14Department of Chemistry and Institute for Drug Discovery, Purdue UniversityDivision of Pulmonary and Critical Care Medicine, Brigham and Women's Hospital, Harvard Medical SchoolDepartment of Chemistry and Institute for Drug Discovery, Purdue UniversityDepartment of Chemistry and Institute for Drug Discovery, Purdue UniversityDepartment of Chemistry and Institute for Drug Discovery, Purdue UniversityDepartment of Chemistry and Institute for Drug Discovery, Purdue UniversityDepartment of Chemistry and Institute for Drug Discovery, Purdue UniversityDepartment of Chemistry and Institute for Drug Discovery, Purdue UniversityDepartment of Chemistry and Institute for Drug Discovery, Purdue UniversityDepartment of Chemistry and Institute for Drug Discovery, Purdue UniversityDepartment of Comparative Pathobiology, Purdue College of Veterinary MedicineDivision of Pulmonary and Critical Care Medicine, Brigham and Women's Hospital, Harvard Medical SchoolThree Lakes PartnersDivision of Pulmonary and Critical Care Medicine, Brigham and Women's Hospital, Harvard Medical SchoolDepartment of Chemistry and Institute for Drug Discovery, Purdue UniversityAbstract Fibrotic diseases cause organ failure that lead to ~45% of all deaths in the United States. Activated macrophages stimulate fibrosis by secreting cytokines that induce fibroblasts to synthesize collagen and extracellular matrix proteins. Although suppression of macrophage‐derived cytokine production can halt progression of fibrosis, therapeutic agents that prevent release of these cytokines (e.g., TLR7 agonists) have proven too toxic to administer systemically. Based on the expression of folate receptor β solely on activated myeloid cells, we have created a folate‐targeted TLR7 agonist (FA‐TLR7‐54) that selectively accumulates in profibrotic macrophages and suppresses fibrosis‐inducing cytokine production. We demonstrate that FA‐TLR7‐54 reprograms M2‐like fibrosis‐inducing macrophages into fibrosis‐suppressing macrophages, resulting in dramatic declines in profibrotic cytokine release, hydroxyproline biosynthesis, and collagen deposition, with concomitant increases in alveolar airspaces. Although nontargeted TLR7‐54 is lethal at fibrosis‐suppressing doses, FA‐TLR7‐54 halts fibrosis without evidence of toxicity. Taken together, FA‐TLR7‐54 is shown to constitute a novel and potent approach for treating fibrosis without causing dose‐limiting systemic toxicities.https://doi.org/10.15252/emmm.202012034bleomycinfolate receptor βidiopathic pulmonary fibrosismacrophagestoll‐like receptor 7 |
| spellingShingle | Fenghua Zhang Ehab A Ayaub Bingbing Wang Estela Puchulu‐Campanella Yen‐Hsing Li Suraj U Hettiarachchi Spencer D Lindeman Qian Luo Sasmita Rout Madduri Srinivasarao Abigail Cox Konstantin Tsoyi Cheryl Nickerson‐Nutter Ivan O Rosas Philip S Low Reprogramming of profibrotic macrophages for treatment of bleomycin‐induced pulmonary fibrosis EMBO Molecular Medicine bleomycin folate receptor β idiopathic pulmonary fibrosis macrophages toll‐like receptor 7 |
| title | Reprogramming of profibrotic macrophages for treatment of bleomycin‐induced pulmonary fibrosis |
| title_full | Reprogramming of profibrotic macrophages for treatment of bleomycin‐induced pulmonary fibrosis |
| title_fullStr | Reprogramming of profibrotic macrophages for treatment of bleomycin‐induced pulmonary fibrosis |
| title_full_unstemmed | Reprogramming of profibrotic macrophages for treatment of bleomycin‐induced pulmonary fibrosis |
| title_short | Reprogramming of profibrotic macrophages for treatment of bleomycin‐induced pulmonary fibrosis |
| title_sort | reprogramming of profibrotic macrophages for treatment of bleomycin induced pulmonary fibrosis |
| topic | bleomycin folate receptor β idiopathic pulmonary fibrosis macrophages toll‐like receptor 7 |
| url | https://doi.org/10.15252/emmm.202012034 |
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