Novel protein pathways in development and progression of pulmonary sarcoidosis

Maneesh Bhargava; K. J. Viken; B. Barkes; T. J. Griffin; M. Gillespie; P. D. Jagtap; R. Sajulga; E. J. Peterson; H. E. Dincer; L. Li; C. I. Restrepo; B. P. O’Connor; T. E. Fingerlin; D. M. Perlman; L. A. Maier

doi:10.1038/s41598-020-69281-8

Novel protein pathways in development and progression of pulmonary sarcoidosis

Maneesh Bhargava, K. J. Viken, B. Barkes, T. J. Griffin, M. Gillespie, P. D. Jagtap, R. Sajulga, E. J. Peterson, H. E. Dincer, L. Li, C. I. Restrepo, B. P. O’Connor, T. E. Fingerlin, D. M. Perlman, L. A. Maier

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Abstract

Pulmonary involvement occurs in up to 95% of sarcoidosis cases. In this pilot study, we examine lung compartment-specific protein expression to identify pathways linked to development and progression of pulmonary sarcoidosis. We characterized bronchoalveolar lavage (BAL) cells and fluid (BALF) proteins in recently diagnosed sarcoidosis cases. We identified 4,306 proteins in BAL cells, of which 272 proteins were differentially expressed in sarcoidosis compared to controls. These proteins map to novel pathways such as integrin-linked kinase and IL-8 signaling and previously implicated pathways in sarcoidosis, including phagosome maturation, clathrin-mediated endocytic signaling and redox balance. In the BALF, the differentially expressed proteins map to several pathways identified in the BAL cells. The differentially expressed BALF proteins also map to aryl hydrocarbon signaling, communication between innate and adaptive immune response, integrin, PTEN and phospholipase C signaling, serotonin and tryptophan metabolism, autophagy, and B cell receptor signaling. Additional pathways that were different between progressive and non-progressive sarcoidosis in the BALF included CD28 signaling and PFKFB4 signaling. Our studies demonstrate the power of contemporary proteomics to reveal novel mechanisms operational in sarcoidosis. Application of our workflows in well-phenotyped large cohorts maybe beneficial to identify biomarkers for diagnosis and prognosis and therapeutically tenable molecular mechanisms.

Original language	English (US)
Article number	13282
Journal	Scientific reports
Volume	10
Issue number	1
DOIs	https://doi.org/10.1038/s41598-020-69281-8
State	Published - Dec 1 2020

Bibliographical note

Funding Information:
The authors greatly appreciate the patients and the research participants. They also thank the personnel at the Center for Mass Spectrometry and Proteomics, especially LeeAnn Higgins and Todd Markowski for MS analysis. The Minnesota Supercomputing Institute maintains GalaxyP at the University of Minnesota, and the infrastructure is supported by National Cancer Institute Grant U24CA199347 (TJG). Lee S Parsons PhD assisted in implementing Maxquant on Mesabi servers at Minnesota Supercomputing Institute. The project was supported by the University of Minnesota Department of Medicine and the Division of Pulmonary and Critical Care (MB), Sarcoidosis Research and Education Foundation (MB), R01ES023826 (LAM. LL), R01HL140357 (LAM), U01 HL112695 and UL1TR002535 (LAM)

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Bhargava, M., Viken, K. J., Barkes, B., Griffin, T. J., Gillespie, M., Jagtap, P. D., Sajulga, R., Peterson, E. J., Dincer, H. E., Li, L., Restrepo, C. I., O’Connor, B. P., Fingerlin, T. E., Perlman, D. M., & Maier, L. A. (2020). Novel protein pathways in development and progression of pulmonary sarcoidosis. Scientific reports, 10(1), Article 13282. https://doi.org/10.1038/s41598-020-69281-8

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abstract = "Pulmonary involvement occurs in up to 95% of sarcoidosis cases. In this pilot study, we examine lung compartment-specific protein expression to identify pathways linked to development and progression of pulmonary sarcoidosis. We characterized bronchoalveolar lavage (BAL) cells and fluid (BALF) proteins in recently diagnosed sarcoidosis cases. We identified 4,306 proteins in BAL cells, of which 272 proteins were differentially expressed in sarcoidosis compared to controls. These proteins map to novel pathways such as integrin-linked kinase and IL-8 signaling and previously implicated pathways in sarcoidosis, including phagosome maturation, clathrin-mediated endocytic signaling and redox balance. In the BALF, the differentially expressed proteins map to several pathways identified in the BAL cells. The differentially expressed BALF proteins also map to aryl hydrocarbon signaling, communication between innate and adaptive immune response, integrin, PTEN and phospholipase C signaling, serotonin and tryptophan metabolism, autophagy, and B cell receptor signaling. Additional pathways that were different between progressive and non-progressive sarcoidosis in the BALF included CD28 signaling and PFKFB4 signaling. Our studies demonstrate the power of contemporary proteomics to reveal novel mechanisms operational in sarcoidosis. Application of our workflows in well-phenotyped large cohorts maybe beneficial to identify biomarkers for diagnosis and prognosis and therapeutically tenable molecular mechanisms.",

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note = "Funding Information: The authors greatly appreciate the patients and the research participants. They also thank the personnel at the Center for Mass Spectrometry and Proteomics, especially LeeAnn Higgins and Todd Markowski for MS analysis. The Minnesota Supercomputing Institute maintains GalaxyP at the University of Minnesota, and the infrastructure is supported by National Cancer Institute Grant U24CA199347 (TJG). Lee S Parsons PhD assisted in implementing Maxquant on Mesabi servers at Minnesota Supercomputing Institute. The project was supported by the University of Minnesota Department of Medicine and the Division of Pulmonary and Critical Care (MB), Sarcoidosis Research and Education Foundation (MB), R01ES023826 (LAM. LL), R01HL140357 (LAM), U01 HL112695 and UL1TR002535 (LAM) Publisher Copyright: {\textcopyright} 2020, The Author(s).",

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AU - Viken, K. J.

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AU - Griffin, T. J.

AU - Gillespie, M.

AU - Jagtap, P. D.

AU - Sajulga, R.

AU - Peterson, E. J.

AU - Dincer, H. E.

AU - Li, L.

AU - Restrepo, C. I.

AU - O’Connor, B. P.

AU - Fingerlin, T. E.

AU - Perlman, D. M.

AU - Maier, L. A.

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N2 - Pulmonary involvement occurs in up to 95% of sarcoidosis cases. In this pilot study, we examine lung compartment-specific protein expression to identify pathways linked to development and progression of pulmonary sarcoidosis. We characterized bronchoalveolar lavage (BAL) cells and fluid (BALF) proteins in recently diagnosed sarcoidosis cases. We identified 4,306 proteins in BAL cells, of which 272 proteins were differentially expressed in sarcoidosis compared to controls. These proteins map to novel pathways such as integrin-linked kinase and IL-8 signaling and previously implicated pathways in sarcoidosis, including phagosome maturation, clathrin-mediated endocytic signaling and redox balance. In the BALF, the differentially expressed proteins map to several pathways identified in the BAL cells. The differentially expressed BALF proteins also map to aryl hydrocarbon signaling, communication between innate and adaptive immune response, integrin, PTEN and phospholipase C signaling, serotonin and tryptophan metabolism, autophagy, and B cell receptor signaling. Additional pathways that were different between progressive and non-progressive sarcoidosis in the BALF included CD28 signaling and PFKFB4 signaling. Our studies demonstrate the power of contemporary proteomics to reveal novel mechanisms operational in sarcoidosis. Application of our workflows in well-phenotyped large cohorts maybe beneficial to identify biomarkers for diagnosis and prognosis and therapeutically tenable molecular mechanisms.

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Novel protein pathways in development and progression of pulmonary sarcoidosis

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