Journal article
Muscle inflammation is regulated by NF-κB from multiple cells to control distinct states of wasting in cancer cachexia
Cell reports (Cambridge), Vol.43(11), 114925
11/01/2024
DOI: 10.1016/j.celrep.2024.114925
PMCID: PMC11774514
PMID: 39475511
Abstract
Although cancer cachexia is classically characterized as a systemic inflammatory disorder, emerging evidence indicates that weight loss also associates with local tissue inflammation. We queried the regulation of this inflammation and its causality to cachexia by exploring skeletal muscle, whose atrophy strongly associates with poor outcomes. Using multiple mouse models and patient samples, we show that cachectic muscle is marked by enhanced innate immunity. Nuclear factor κB (NF-κB) activity in multiple cells, including satellite cells, myofibers, and fibro-adipogenic progenitors, promotes macrophage expansion equally derived from infiltrating monocytes and resident cells. Moreover, NF-κB-activated cells and macrophages undergo crosstalk; NF-κB+ cells recruit macrophages to inhibit regeneration and promote atrophy but, interestingly, also protect myofibers, while macrophages stimulate NF-κB+ cells to sustain an inflammatory feedforward loop. Together, we propose that NF-κB functions in multiple cells in the muscle microenvironment to stimulate macrophages that both promote and protect against muscle wasting in cancer.
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•Cancer cachexia exhibits muscle inflammation, regulated by NF-κB from multiple cell types•Muscle inflammation in cancer cachexia is mediated by myeloid cells, mostly macrophages•Macrophages in cachectic muscle derive from infiltrating monocytes and resident cells•Heterogeneous populations of macrophages exhibit both pro- and anti-atrophy activities
We demonstrate that NF-κB functions in multiple cells in skeletal muscle to expand macrophages during cancer cachexia, deriving from infiltrating monocytes and resident cells. Macrophages contribute to muscle wasting and preservation of myofibers. They also crosstalk with muscle stem cells, myofibers, and fibro-adipogenic progenitors to sustain NF-κB activity and inflammation.
Details
- Title: Subtitle
- Muscle inflammation is regulated by NF-κB from multiple cells to control distinct states of wasting in cancer cachexia
- Creators
- Benjamin R. Pryce - Medical University of South CarolinaAlexander Oles - Medical University of South CarolinaErin E. Talbert - University of IowaMartin J. Romeo - MUSC Hollings Cancer CenterSilvia Vaena - MUSC Hollings Cancer CenterSudarshana Sharma - Medical University of South CarolinaVictoria Spadafora - Medical University of South CarolinaLauren Tolliver - Medical University of South CarolinaDavid A. Mahvi - Medical University of South CarolinaKatherine A. Morgan - Medical University of South CarolinaWilliam P. Lancaster - Medical University of South CarolinaEryn Beal - Medical University of South CarolinaNatlie Koren - Medical University of South CarolinaBailey Watts - Medical University of South CarolinaMorgan Overstreet - Medical University of South CarolinaStefano Berto - Medical University of South CarolinaSuganya Subramanian - Medical University of South CarolinaKubra Calisir - Medical University of South CarolinaAnna Crawford - Medical University of South CarolinaMichael C. Ostrowski - MUSC Hollings Cancer CenterBrian Neelon - MUSC Hollings Cancer CenterTeresa A. Zimmers - Oregon Health & Science UniversityJames G. Tidball - University of California, Los AngelesDavid J. Wang - Medical University of South CarolinaDenis C. Guttridge - MUSC Hollings Cancer Center
- Resource Type
- Journal article
- Publication Details
- Cell reports (Cambridge), Vol.43(11), 114925
- DOI
- 10.1016/j.celrep.2024.114925
- PMID
- 39475511
- PMCID
- PMC11774514
- NLM abbreviation
- Cell Rep
- ISSN
- 2211-1247
- eISSN
- 2211-1247
- Publisher
- Elsevier Inc
- Grant note
- NIH/NCI P30 Cancer Center Support Grant: CA13813 NIH/NCI P01 grant: CA236778
We thank members of the Guttridge laboratory for their helpful discussions throughout this study. We are also grateful to members of our PDAC cachexia P01 team for their continuing support and feedback given to this project, as well as The Ohio State University Comprehensive Cancer Center Cancer Cachexia Program, who provided patient samples. We thank Dr. Michael Karin for sharing IKKb conditional mice, as well as other colleagues who generated the mutant mice used in our study. Funding support was provided by an NIH/NIAMS R01 grant AR072714 to D.C.G., J.G.T., and D.J.W.; a Hollings Cancer Center Postdoctoral Fellowship Award to B.R.P.; an NIH/NCI F30 grant CA265071 to A.O.; an NIH/NIAMS R00 grant AR071508 to E.E.T.; NIH/NCI R01 grants CA122596 and CA194593, VA awards I01BX004177 and I01CX002046,an NIH/NCI P30 Cancer Center Support Grant P30 CA082709 to T.A.Z; an NIH/NCI P30 Cancer Center Support Grant CA13813 to M.C.O. and D.C.G.; and an NIH/NCI P01 grant CA236778 to T.A.Z., M.C.O., and D.C.G.
- Language
- English
- Date published
- 11/01/2024
- Academic Unit
- Molecular Physiology and Biophysics; Fraternal Order of Eagles Diabetes Research Center; Health, Sport, and Human Physiology ; Internal Medicine
- Record Identifier
- 9984742653802771
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