TY - JOUR
T1 - Influenza A virus infection induces muscle wasting via IL-6 regulation of the E3 ubiquitin ligase atrogin-1
AU - Radigan, Kathryn A.
AU - Nicholson, Trevor T.
AU - Welch, Lynn C.
AU - Chi, Monica
AU - Amarelle, Luciano
AU - Angulo, Martín
AU - Shigemura, Masahiko
AU - Shigemura, Atsuko
AU - Runyan, Constance E.
AU - Morales-Nebreda, Luisa
AU - Perlman, Harris
AU - Ceco, Ermelinda
AU - Lecuona, Emilia
AU - Dada, Laura A.
AU - Misharin, Alexander V.
AU - Mutlu, Gokhan M.
AU - Sznajder, Jacob I.
AU - Scott Budinger, G. R.
N1 - Funding Information:
This work was supported by grants from the National Institute on Aging (PO1-AG-49665) and the National Institutes of Health (HL-71643, T32-HL-076139). We thank Angela Pantell and Marina Casalino Matsuda for technical assistance. We are grateful to Regeneron Pharmaceuticals for providing the atrogin-1 mice. Histology services were provided by the Northwestern University Mouse Histology and Phenotyping Laboratory, which is supported by National Cancer Institute P30 CA060553, awarded to the Robert H. Lurie Comprehensive Cancer Center. Imaging work was performed at the Northwestern University Center for Advanced Microscopy, which is generously supported by National Cancer Institute Cancer Center Support Grant P30 CA060553, awarded to the Robert H. Lurie Comprehensive Cancer Center.
Funding Information:
We thank Angela Pantell and Marina Casalino Matsuda for technical assistance. We are grateful to Regeneron Pharmaceuticals for providing the atrogin-1 mice. Histology services were provided by the Northwestern University Mouse Histology and Phenotyping Laboratory, which is supported by National Cancer Institute P30 CA060553, awarded to the Robert H. Lurie Comprehensive Cancer Center. Imaging work was performed at the Northwestern University Center for Advanced Microscopy, which is generously supported by National Cancer Institute Cancer Center Support Grant P30 CA060553, awarded to the Robert H. Lurie Comprehensive Cancer Center.
Funding Information:
This work was supported by grants from the National Institute on Aging (PO1-AG-49665) and the National Institutes of Health (HL-71643, T32-HL-076139).
Publisher Copyright:
Copyright © 2019 by The American Association of Immunologists, Inc.
PY - 2019/1/15
Y1 - 2019/1/15
N2 - Muscle dysfunction is common in patients with adult respiratory distress syndrome and is associated with morbidity that can persist for years after discharge. In a mouse model of severe influenza A pneumonia, we found the proinflammatory cytokine IL-6 was necessary for the development of muscle dysfunction. Treatment with a Food and Drug Administration–approved Ab antagonist to the IL-6R (tocilizumab) attenuated the severity of influenza A–induced muscle dysfunction. In cultured myotubes, IL-6 promoted muscle degradation via JAK/STAT, FOXO3a, and atrogin-1 upregulation. Consistent with these findings, atrogin-1 +/2 and atrogin-1 2 / 2 mice had attenuated muscle dysfunction following influenza infection. Our data suggest that inflammatory endocrine signals originating from the injured lung activate signaling pathways in the muscle that induce dysfunction. Inhibiting these pathways may limit morbidity in patients with influenza A pneumonia and adult respiratory distress syndrome.
AB - Muscle dysfunction is common in patients with adult respiratory distress syndrome and is associated with morbidity that can persist for years after discharge. In a mouse model of severe influenza A pneumonia, we found the proinflammatory cytokine IL-6 was necessary for the development of muscle dysfunction. Treatment with a Food and Drug Administration–approved Ab antagonist to the IL-6R (tocilizumab) attenuated the severity of influenza A–induced muscle dysfunction. In cultured myotubes, IL-6 promoted muscle degradation via JAK/STAT, FOXO3a, and atrogin-1 upregulation. Consistent with these findings, atrogin-1 +/2 and atrogin-1 2 / 2 mice had attenuated muscle dysfunction following influenza infection. Our data suggest that inflammatory endocrine signals originating from the injured lung activate signaling pathways in the muscle that induce dysfunction. Inhibiting these pathways may limit morbidity in patients with influenza A pneumonia and adult respiratory distress syndrome.
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U2 - 10.4049/jimmunol.1701433
DO - 10.4049/jimmunol.1701433
M3 - Article
C2 - 30530483
AN - SCOPUS:85059928675
VL - 202
SP - 484
EP - 493
JO - Journal of Immunology
JF - Journal of Immunology
SN - 0022-1767
IS - 2
ER -