دورية أكاديمية
Mycobacterial Infection is Promoted by Neutral Sphingomyelinase 2 Regulating a Signaling Cascade Leading to Activation of β1-Integrin
| العنوان: | Mycobacterial Infection is Promoted by Neutral Sphingomyelinase 2 Regulating a Signaling Cascade Leading to Activation of β1-Integrin |
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| المؤلفون: | Yuqing Wu, Cao Li, Andrea Riehle, Barbara Pollmeier, Erich Gulbins, Heike Grassmé |
| المصدر: | Cellular Physiology and Biochemistry, Vol 51, Iss 4, Pp 1815-1829 (2018) |
| بيانات النشر: | Cell Physiol Biochem Press GmbH & Co KG, 2018. |
| سنة النشر: | 2018 |
| المجموعة: | LCC:Physiology LCC:Biochemistry |
| مصطلحات موضوعية: | Mycobacterium bovis Bacillus Calmette-Guérin (BCG), Neutral sphingomyelinase 2, Ceramide, Macrophages, Migration, β1-integrin, Rac1, Granuloma, Physiology, QP1-981, Biochemistry, QD415-436 |
| الوصف: | Background/Aims: Mycobacteria-induced diseases, especially tuberculosis, cause more than 1 million deaths each year, which is higher than any other single bacterial pathogen. Neutral sphingomyelinase 2 (Nsm2) has been implied in many physiological processes and diseases, but the role of Nsm2 in pathogen-host interactions and mycobacterial infections has barely been studied. Methods: We investigated the role of the Nsm2/ceramide system in systemic infection of mice and murine macrophages with Mycobacterium bovis Bacillus Calmette-Guérin (BCG) as a model for mycobacterial infection. For in vitro assays we isolated bone marrow-derived macrophages from Wildtype mice or Nsm2-heterozygous and investigated the role of Nsm2 for macrophage migration/clustering as well as the involvement of p38 mitogen-activated protein kinases (p38K), c-Jun N-terminal kinase (JNK), β1-integrin and Rac1 activity by Western blot and microscopic studies. For in vivo assays we injected mice intravenously with BCG and analyzed infected tissues for the role of Nsm2-mediated activation of β1-integrin in granuloma formation and bacterial burden. Results: Our results reveal that BCG infection of macrophages results in rapid stimulation of Nsm2. Genetic and pharmacological studies demonstrate that Nsm2 stimulates a signaling cascade via p38K and JNK to an activation of surface β1-integrin and Rac1 that leads to the formation of granuloma-like macrophages clusters in vitro and granuloma in vivo. Heterozygosity of Nsm2 in macrophages or antibody-mediated neutralization of active b1-integrin reduced macrophage clusters in vitro and granuloma formation in vivo. Most importantly, Nsm2 heterozygosity or treatment with neutralizing antibodies against β1-integrin protected mice from systemic BCG infections and chronic infections of the liver and spleen. Conclusion: The findings indicate that the Nsm2/ ceramide system plays an important role in systemic infection of mice with mycobacteria by regulating a signaling cascade via p38K, JNK, b1-integrin and Rac1. |
| نوع الوثيقة: | article |
| وصف الملف: | electronic resource |
| اللغة: | English |
| تدمد: | 1015-8987 1421-9778 |
| العلاقة: | https://www.karger.com/Article/FullText/495683Test; https://doaj.org/toc/1015-8987Test; https://doaj.org/toc/1421-9778Test |
| DOI: | 10.1159/000495683 |
| الوصول الحر: | https://doaj.org/article/20551a25617140438f03b074357c4c83Test |
| رقم الانضمام: | edsdoj.20551a25617140438f03b074357c4c83 |
| قاعدة البيانات: | Directory of Open Access Journals |
| تدمد: | 10158987 14219778 |
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| DOI: | 10.1159/000495683 |