ACK1 Contributes to the Pathogenesis of Inflammation and Autoimmunity by Promoting the Activation of TLR Signaling Pathways
Toll-like receptors (TLRs) are the first line of defense in the immune system, whose activation plays a key role in the pathogenesis of inflammation and autoimmunity. TLRs can activate a variety of immune cells such as macrophages and dendritic cells, which produce proinflammatory cytokines, chemoki...
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| Format: | Article |
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Frontiers Media S.A.
2022-05-01
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| Series: | Frontiers in Immunology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fimmu.2022.864995/full |
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| author | Lina Jing Lina Jing Xin Zhang Xin Zhang Dong Liu Yonghong Yang Huabao Xiong Huabao Xiong Guanjun Dong Guanjun Dong |
| author_facet | Lina Jing Lina Jing Xin Zhang Xin Zhang Dong Liu Yonghong Yang Huabao Xiong Huabao Xiong Guanjun Dong Guanjun Dong |
| author_sort | Lina Jing |
| collection | DOAJ |
| description | Toll-like receptors (TLRs) are the first line of defense in the immune system, whose activation plays a key role in the pathogenesis of inflammation and autoimmunity. TLRs can activate a variety of immune cells such as macrophages and dendritic cells, which produce proinflammatory cytokines, chemokines, and co-stimulatory molecules that lead to the development of inflammation and autoimmune diseases. As a nonreceptor tyrosine kinase, ACK1 is involved in multiple signaling pathways and physiological processes. However, the roles of ACK1 in the activation of TLR pathways and in the pathogenesis of inflammation and autoimmune diseases have not yet been reported. We found that the expression of ACK1 could be upregulated by TLR pathways in vivo and in vitro. Intriguingly, overexpression of ACK1 significantly promoted the activation of TLR4, TLR7, and TLR9 pathways, while knockdown of ACK1 or the use of the ACK1 inhibitor AIM-100 significantly inhibited the activation of TLR4, TLR7, and TLR9 pathways. In vivo studies showed that the inhibition of ACK1 activity by AIM-100 could significantly protect mice from the TLR4 agonist lipopolysaccharide (LPS)-mediated endotoxin shock and alleviate the condition of imiquimod-mediated lupus-prone mice and MRL/lpr mice. In summary, ACK1 participates in TLR-mediated inflammation and autoimmunity and has great potential in controlling inflammation and alleviating autoimmune diseases. |
| first_indexed | 2024-12-12T06:38:11Z |
| format | Article |
| id | doaj.art-bf429ce439b14123b8b7c6f68950ec30 |
| institution | Directory Open Access Journal |
| issn | 1664-3224 |
| language | English |
| last_indexed | 2024-12-12T06:38:11Z |
| publishDate | 2022-05-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Immunology |
| spelling | doaj.art-bf429ce439b14123b8b7c6f68950ec302022-12-22T00:34:25ZengFrontiers Media S.A.Frontiers in Immunology1664-32242022-05-011310.3389/fimmu.2022.864995864995ACK1 Contributes to the Pathogenesis of Inflammation and Autoimmunity by Promoting the Activation of TLR Signaling PathwaysLina Jing0Lina Jing1Xin Zhang2Xin Zhang3Dong Liu4Yonghong Yang5Huabao Xiong6Huabao Xiong7Guanjun Dong8Guanjun Dong9Cheeloo College of Medicine, Shandong University, Jinan, ChinaInstitute of Immunology and Molecular Medicine, Jining Medical University, Jining, ChinaInstitute of Immunology and Molecular Medicine, Jining Medical University, Jining, ChinaSchool of Medical Laboratory, Weifang Medical University, Weifang, ChinaDepartment of Clinical Laboratory, Affiliated Hospital of Jining Medical University, Jining, ChinaMedical Research Center, Affiliated Hospital of Jining Medical University, Jining, ChinaInstitute of Immunology and Molecular Medicine, Jining Medical University, Jining, ChinaJining Key Laboratory of Immunology, Jining Medical University, Jining, ChinaInstitute of Immunology and Molecular Medicine, Jining Medical University, Jining, ChinaJining Key Laboratory of Immunology, Jining Medical University, Jining, ChinaToll-like receptors (TLRs) are the first line of defense in the immune system, whose activation plays a key role in the pathogenesis of inflammation and autoimmunity. TLRs can activate a variety of immune cells such as macrophages and dendritic cells, which produce proinflammatory cytokines, chemokines, and co-stimulatory molecules that lead to the development of inflammation and autoimmune diseases. As a nonreceptor tyrosine kinase, ACK1 is involved in multiple signaling pathways and physiological processes. However, the roles of ACK1 in the activation of TLR pathways and in the pathogenesis of inflammation and autoimmune diseases have not yet been reported. We found that the expression of ACK1 could be upregulated by TLR pathways in vivo and in vitro. Intriguingly, overexpression of ACK1 significantly promoted the activation of TLR4, TLR7, and TLR9 pathways, while knockdown of ACK1 or the use of the ACK1 inhibitor AIM-100 significantly inhibited the activation of TLR4, TLR7, and TLR9 pathways. In vivo studies showed that the inhibition of ACK1 activity by AIM-100 could significantly protect mice from the TLR4 agonist lipopolysaccharide (LPS)-mediated endotoxin shock and alleviate the condition of imiquimod-mediated lupus-prone mice and MRL/lpr mice. In summary, ACK1 participates in TLR-mediated inflammation and autoimmunity and has great potential in controlling inflammation and alleviating autoimmune diseases.https://www.frontiersin.org/articles/10.3389/fimmu.2022.864995/fullACK1TLRmacrophagesdendritic cellsinflammationautoimmunity |
| spellingShingle | Lina Jing Lina Jing Xin Zhang Xin Zhang Dong Liu Yonghong Yang Huabao Xiong Huabao Xiong Guanjun Dong Guanjun Dong ACK1 Contributes to the Pathogenesis of Inflammation and Autoimmunity by Promoting the Activation of TLR Signaling Pathways Frontiers in Immunology ACK1 TLR macrophages dendritic cells inflammation autoimmunity |
| title | ACK1 Contributes to the Pathogenesis of Inflammation and Autoimmunity by Promoting the Activation of TLR Signaling Pathways |
| title_full | ACK1 Contributes to the Pathogenesis of Inflammation and Autoimmunity by Promoting the Activation of TLR Signaling Pathways |
| title_fullStr | ACK1 Contributes to the Pathogenesis of Inflammation and Autoimmunity by Promoting the Activation of TLR Signaling Pathways |
| title_full_unstemmed | ACK1 Contributes to the Pathogenesis of Inflammation and Autoimmunity by Promoting the Activation of TLR Signaling Pathways |
| title_short | ACK1 Contributes to the Pathogenesis of Inflammation and Autoimmunity by Promoting the Activation of TLR Signaling Pathways |
| title_sort | ack1 contributes to the pathogenesis of inflammation and autoimmunity by promoting the activation of tlr signaling pathways |
| topic | ACK1 TLR macrophages dendritic cells inflammation autoimmunity |
| url | https://www.frontiersin.org/articles/10.3389/fimmu.2022.864995/full |
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