Nogo-A Is Critical for Pro-Inflammatory Gene Regulation in Myocytes and Macrophages
Nogo-A (Rtn 4A), a member of the reticulon 4 (Rtn4) protein family, is a neurite outgrowth inhibitor protein that is primarily expressed in the central nervous system (CNS). However, previous studies revealed that Nogo-A was upregulated in skeletal muscles of Amyotrophic lateral sclerosis (ALS) pati...
| Main Authors: | , , , , , , , , , , , , , , |
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MDPI AG
2021-01-01
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| author | H. M. Arif Ullah A. K. Elfadl SunYoung Park Yong Deuk Kim Myung-Jin Chung Ji-Yoon Son Hyun-Ho Yun Jae-Min Park Jae-Hyuk Yim Seung-Jun Jung Young-Chul Choi Jin-Hong Shin Dae-Seong Kim Jin-Kyu Park Kyu-Shik Jeong |
| author_facet | H. M. Arif Ullah A. K. Elfadl SunYoung Park Yong Deuk Kim Myung-Jin Chung Ji-Yoon Son Hyun-Ho Yun Jae-Min Park Jae-Hyuk Yim Seung-Jun Jung Young-Chul Choi Jin-Hong Shin Dae-Seong Kim Jin-Kyu Park Kyu-Shik Jeong |
| author_sort | H. M. Arif Ullah |
| collection | DOAJ |
| description | Nogo-A (Rtn 4A), a member of the reticulon 4 (Rtn4) protein family, is a neurite outgrowth inhibitor protein that is primarily expressed in the central nervous system (CNS). However, previous studies revealed that Nogo-A was upregulated in skeletal muscles of Amyotrophic lateral sclerosis (ALS) patients. Additionally, experiments showed that endoplasmic reticulum (ER) stress marker, C/EBP homologous protein (CHOP), was upregulated in gastrocnemius muscle of a murine model of ALS. We therefore hypothesized that Nogo-A might relate to skeletal muscle diseases. According to our knocking down and overexpression results in muscle cell line (C2C12), we have found that upregulation of Nogo-A resulted in upregulation of CHOP, pro-inflammatory cytokines such as interleukin (IL)-6 and tumor necrosis factor (TNF)-α, while downregulation of Nogo-A led to downregulation of CHOP, IL-6 and TNF-α. Immunofluorescence results showed that Nogo-A and CHOP were expressed by myofibers as well as tissue macrophages. Since resident macrophages share similar functions as bone marrow-derived macrophages (BMDM), we therefore, isolated macrophages from bone marrow to study the role of Nogo-A in activation of these cells. Lipopolysaccharide (LPS)-stimulated BMDM in Nogo-KO mice showed low mRNA expression of CHOP, IL-6 and TNF-α compared to BMDM in wild type (WT) mice. Interestingly, Nogo knockout (KO) BMDM exhibited lower migratory activity and phagocytic ability compared with WT BMDM after LPS treatment. In addition, mice experiments data revealed that upregulation of Nogo-A in notexin- and tunicamycin-treated muscles was associated with upregulation of CHOP, IL-6 and TNF-α in WT group, while in Nogo-KO group resulted in low expression level of CHOP, IL-6 and TNF-α. Furthermore, upregulation of Nogo-A in dystrophin-deficient (mdx) murine model, myopathy and Duchenne muscle dystrophy (DMD) clinical biopsies was associated with upregulation of CHOP, IL-6 and TNF-α. To the best of our knowledge, this is the first study to demonstrate Nogo-A as a regulator of inflammation in diseased muscle and bone marrow macrophages and that deletion of Nogo-A alleviates muscle inflammation and it can be utilized as a therapeutic target for improving muscle diseases. |
| first_indexed | 2024-03-09T06:20:54Z |
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| last_indexed | 2024-03-09T06:20:54Z |
| publishDate | 2021-01-01 |
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| spelling | doaj.art-92795c41ddb84c5d98266c0f090d78992023-12-03T11:48:03ZengMDPI AGCells2073-44092021-01-0110228210.3390/cells10020282Nogo-A Is Critical for Pro-Inflammatory Gene Regulation in Myocytes and MacrophagesH. M. Arif Ullah0A. K. Elfadl1SunYoung Park2Yong Deuk Kim3Myung-Jin Chung4Ji-Yoon Son5Hyun-Ho Yun6Jae-Min Park7Jae-Hyuk Yim8Seung-Jun Jung9Young-Chul Choi10Jin-Hong Shin11Dae-Seong Kim12Jin-Kyu Park13Kyu-Shik Jeong14Department of Pathology, College of Veterinary Medicine, Kyungpook National University, Daegu 41566, KoreaDepartment of Pathology, College of Veterinary Medicine, Kyungpook National University, Daegu 41566, KoreaDepartment of Pathology, College of Veterinary Medicine, Kyungpook National University, Daegu 41566, KoreaSchool of Applied Biosciences, Kyungpook National University, Daegu 41566, KoreaDepartment of Pathology, College of Veterinary Medicine, Kyungpook National University, Daegu 41566, KoreaDepartment of Pathology, College of Veterinary Medicine, Kyungpook National University, Daegu 41566, KoreaDepartment of Pathology, College of Veterinary Medicine, Kyungpook National University, Daegu 41566, KoreaDepartment of Pathology, College of Veterinary Medicine, Kyungpook National University, Daegu 41566, KoreaDepartment of Pathology, College of Veterinary Medicine, Kyungpook National University, Daegu 41566, KoreaDepartment of Pathology, College of Veterinary Medicine, Kyungpook National University, Daegu 41566, KoreaDepartment of Neurology, Gangnam Severance Hospital, Yonsei University College of Medicine, Seoul 03722, KoreaDepartment of Neurology, Pusan National University Yangsan hospital, Yangsan 50612, KoreaDepartment of Neurology, Pusan National University Yangsan hospital, Yangsan 50612, KoreaDepartment of Pathology, College of Veterinary Medicine, Kyungpook National University, Daegu 41566, KoreaDepartment of Pathology, College of Veterinary Medicine, Kyungpook National University, Daegu 41566, KoreaNogo-A (Rtn 4A), a member of the reticulon 4 (Rtn4) protein family, is a neurite outgrowth inhibitor protein that is primarily expressed in the central nervous system (CNS). However, previous studies revealed that Nogo-A was upregulated in skeletal muscles of Amyotrophic lateral sclerosis (ALS) patients. Additionally, experiments showed that endoplasmic reticulum (ER) stress marker, C/EBP homologous protein (CHOP), was upregulated in gastrocnemius muscle of a murine model of ALS. We therefore hypothesized that Nogo-A might relate to skeletal muscle diseases. According to our knocking down and overexpression results in muscle cell line (C2C12), we have found that upregulation of Nogo-A resulted in upregulation of CHOP, pro-inflammatory cytokines such as interleukin (IL)-6 and tumor necrosis factor (TNF)-α, while downregulation of Nogo-A led to downregulation of CHOP, IL-6 and TNF-α. Immunofluorescence results showed that Nogo-A and CHOP were expressed by myofibers as well as tissue macrophages. Since resident macrophages share similar functions as bone marrow-derived macrophages (BMDM), we therefore, isolated macrophages from bone marrow to study the role of Nogo-A in activation of these cells. Lipopolysaccharide (LPS)-stimulated BMDM in Nogo-KO mice showed low mRNA expression of CHOP, IL-6 and TNF-α compared to BMDM in wild type (WT) mice. Interestingly, Nogo knockout (KO) BMDM exhibited lower migratory activity and phagocytic ability compared with WT BMDM after LPS treatment. In addition, mice experiments data revealed that upregulation of Nogo-A in notexin- and tunicamycin-treated muscles was associated with upregulation of CHOP, IL-6 and TNF-α in WT group, while in Nogo-KO group resulted in low expression level of CHOP, IL-6 and TNF-α. Furthermore, upregulation of Nogo-A in dystrophin-deficient (mdx) murine model, myopathy and Duchenne muscle dystrophy (DMD) clinical biopsies was associated with upregulation of CHOP, IL-6 and TNF-α. To the best of our knowledge, this is the first study to demonstrate Nogo-A as a regulator of inflammation in diseased muscle and bone marrow macrophages and that deletion of Nogo-A alleviates muscle inflammation and it can be utilized as a therapeutic target for improving muscle diseases.https://www.mdpi.com/2073-4409/10/2/282Nogo-AinflammationCHOPmacrophagespro-inflammatory factors |
| spellingShingle | H. M. Arif Ullah A. K. Elfadl SunYoung Park Yong Deuk Kim Myung-Jin Chung Ji-Yoon Son Hyun-Ho Yun Jae-Min Park Jae-Hyuk Yim Seung-Jun Jung Young-Chul Choi Jin-Hong Shin Dae-Seong Kim Jin-Kyu Park Kyu-Shik Jeong Nogo-A Is Critical for Pro-Inflammatory Gene Regulation in Myocytes and Macrophages Cells Nogo-A inflammation CHOP macrophages pro-inflammatory factors |
| title | Nogo-A Is Critical for Pro-Inflammatory Gene Regulation in Myocytes and Macrophages |
| title_full | Nogo-A Is Critical for Pro-Inflammatory Gene Regulation in Myocytes and Macrophages |
| title_fullStr | Nogo-A Is Critical for Pro-Inflammatory Gene Regulation in Myocytes and Macrophages |
| title_full_unstemmed | Nogo-A Is Critical for Pro-Inflammatory Gene Regulation in Myocytes and Macrophages |
| title_short | Nogo-A Is Critical for Pro-Inflammatory Gene Regulation in Myocytes and Macrophages |
| title_sort | nogo a is critical for pro inflammatory gene regulation in myocytes and macrophages |
| topic | Nogo-A inflammation CHOP macrophages pro-inflammatory factors |
| url | https://www.mdpi.com/2073-4409/10/2/282 |
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