Repurposing drugs to inhibit innate immune responses associated with TLR4, IL1, and NLRP3 signaling in joint cells
Osteoarthritis (OA) affects more than 300 million people worldwide and it is about to become the first disabling disease. OA is characterized by the progressive degradation of the articular cartilage but is a disease of the whole joint. Articular innate immune responses (IIR) associated with tissue...
| Main Authors: | , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Elsevier
2022-11-01
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| Series: | Biomedicine & Pharmacotherapy |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S0753332222010605 |
| _version_ | 1798030956973522944 |
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| author | Eloi Franco-Trepat María Guillán-Fresco Ana Alonso-Pérez Miriam López-Fagúndez Andrés Pazos-Pérez Antia Crespo-Golmar Oreste Gualillo Alberto Jorge-Mora Susana Belén Bravo Rodolfo Gómez |
| author_facet | Eloi Franco-Trepat María Guillán-Fresco Ana Alonso-Pérez Miriam López-Fagúndez Andrés Pazos-Pérez Antia Crespo-Golmar Oreste Gualillo Alberto Jorge-Mora Susana Belén Bravo Rodolfo Gómez |
| author_sort | Eloi Franco-Trepat |
| collection | DOAJ |
| description | Osteoarthritis (OA) affects more than 300 million people worldwide and it is about to become the first disabling disease. OA is characterized by the progressive degradation of the articular cartilage but is a disease of the whole joint. Articular innate immune responses (IIR) associated with tissue degradation contribute to its progression. However, no treatment is available to block these IIRs. Through data text mining and computational pharmacology, we identified two clinical available drugs, naloxone, and thalidomide, with potential inhibitory properties on toll-like receptor 4 (TLR4), a major activator of these IIR. Proteome analysis confirmed that activation of this receptor or the IL1 receptor generated OA-like and gout-like proteomic changes in human primary chondrocytes. Both compounds were found to block TLR4 complex and inhibit TLR4 and IL1R-mediated IIR in OA chondrocytes, osteoblasts, and synoviocytes. Furthermore, naloxone and thalidomide inhibitory effects involved the downregulation of the NLRP3 inflammasome pathway, which is downstream of TLR4/IL1R signaling. We demonstrated that these compounds, within a therapeutic range of concentrations, exhibited anti-inflammatory and anti-catabolic properties in joint primary OA cells without any toxic effect. This data underpins naloxone & thalidomide repurpose to treat OA-associated inflammatory responses. |
| first_indexed | 2024-04-11T19:49:37Z |
| format | Article |
| id | doaj.art-c82a71d6a5344286b231582ba10d64af |
| institution | Directory Open Access Journal |
| issn | 0753-3322 |
| language | English |
| last_indexed | 2024-04-11T19:49:37Z |
| publishDate | 2022-11-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Biomedicine & Pharmacotherapy |
| spelling | doaj.art-c82a71d6a5344286b231582ba10d64af2022-12-22T04:06:21ZengElsevierBiomedicine & Pharmacotherapy0753-33222022-11-01155113671Repurposing drugs to inhibit innate immune responses associated with TLR4, IL1, and NLRP3 signaling in joint cellsEloi Franco-Trepat0María Guillán-Fresco1Ana Alonso-Pérez2Miriam López-Fagúndez3Andrés Pazos-Pérez4Antia Crespo-Golmar5Oreste Gualillo6Alberto Jorge-Mora7Susana Belén Bravo8Rodolfo Gómez9Musculoskeletal Pathology Group, Institute IDIS, Santiago University Clinical Hospital, Santiago de Compostela 15706, SpainMusculoskeletal Pathology Group, Institute IDIS, Santiago University Clinical Hospital, Santiago de Compostela 15706, SpainMusculoskeletal Pathology Group, Institute IDIS, Santiago University Clinical Hospital, Santiago de Compostela 15706, SpainMusculoskeletal Pathology Group, Institute IDIS, Santiago University Clinical Hospital, Santiago de Compostela 15706, SpainMusculoskeletal Pathology Group, Institute IDIS, Santiago University Clinical Hospital, Santiago de Compostela 15706, SpainMusculoskeletal Pathology Group, Institute IDIS, Santiago University Clinical Hospital, Santiago de Compostela 15706, SpainResearch laboratory 9 (NEIRID LAB), Institute of Medical Research, SERGAS, Santiago University Clinical Hospital, Santiago de Compostela 15706, SpainMusculoskeletal Pathology Group, Institute IDIS, Santiago University Clinical Hospital, Santiago de Compostela 15706, SpainProteomics Unit, Institute IDIS, Santiago University Clinical Hospital, Santiago de Compostela 15706, SpainMusculoskeletal Pathology Group, Institute IDIS, Santiago University Clinical Hospital, Santiago de Compostela 15706, Spain; Corresponding author.Osteoarthritis (OA) affects more than 300 million people worldwide and it is about to become the first disabling disease. OA is characterized by the progressive degradation of the articular cartilage but is a disease of the whole joint. Articular innate immune responses (IIR) associated with tissue degradation contribute to its progression. However, no treatment is available to block these IIRs. Through data text mining and computational pharmacology, we identified two clinical available drugs, naloxone, and thalidomide, with potential inhibitory properties on toll-like receptor 4 (TLR4), a major activator of these IIR. Proteome analysis confirmed that activation of this receptor or the IL1 receptor generated OA-like and gout-like proteomic changes in human primary chondrocytes. Both compounds were found to block TLR4 complex and inhibit TLR4 and IL1R-mediated IIR in OA chondrocytes, osteoblasts, and synoviocytes. Furthermore, naloxone and thalidomide inhibitory effects involved the downregulation of the NLRP3 inflammasome pathway, which is downstream of TLR4/IL1R signaling. We demonstrated that these compounds, within a therapeutic range of concentrations, exhibited anti-inflammatory and anti-catabolic properties in joint primary OA cells without any toxic effect. This data underpins naloxone & thalidomide repurpose to treat OA-associated inflammatory responses.http://www.sciencedirect.com/science/article/pii/S0753332222010605TLR4IL1NLRP3OsteoarthritisChondrocytesSynoviocytes |
| spellingShingle | Eloi Franco-Trepat María Guillán-Fresco Ana Alonso-Pérez Miriam López-Fagúndez Andrés Pazos-Pérez Antia Crespo-Golmar Oreste Gualillo Alberto Jorge-Mora Susana Belén Bravo Rodolfo Gómez Repurposing drugs to inhibit innate immune responses associated with TLR4, IL1, and NLRP3 signaling in joint cells Biomedicine & Pharmacotherapy TLR4 IL1 NLRP3 Osteoarthritis Chondrocytes Synoviocytes |
| title | Repurposing drugs to inhibit innate immune responses associated with TLR4, IL1, and NLRP3 signaling in joint cells |
| title_full | Repurposing drugs to inhibit innate immune responses associated with TLR4, IL1, and NLRP3 signaling in joint cells |
| title_fullStr | Repurposing drugs to inhibit innate immune responses associated with TLR4, IL1, and NLRP3 signaling in joint cells |
| title_full_unstemmed | Repurposing drugs to inhibit innate immune responses associated with TLR4, IL1, and NLRP3 signaling in joint cells |
| title_short | Repurposing drugs to inhibit innate immune responses associated with TLR4, IL1, and NLRP3 signaling in joint cells |
| title_sort | repurposing drugs to inhibit innate immune responses associated with tlr4 il1 and nlrp3 signaling in joint cells |
| topic | TLR4 IL1 NLRP3 Osteoarthritis Chondrocytes Synoviocytes |
| url | http://www.sciencedirect.com/science/article/pii/S0753332222010605 |
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