Muscle inflammation is regulated by NF-κB from multiple cells to control distinct states of wasting in cancer cachexia
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<sup>+</sup> cells recruit macrophages to inhibit regeneration and promote atrophy but, interestingly, also protect myofibers, while macrophages stimulate NF-κB<sup>+</sup> 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.
Authors
- James G. Tidball (ORCID: https://orcid.org/0000-0003-1202-8038)
- Silvia G. Vaena
- David A. Mahvi (ORCID: https://orcid.org/0000-0003-2722-8518)
- Erin E. Talbert (ORCID: https://orcid.org/0000-0003-4587-0950)
- Brian Neelon (ORCID: https://orcid.org/0000-0002-8929-6033)
- Alexander Oles (ORCID: https://orcid.org/0000-0001-9348-8524)
- Katherine A. Morgan (ORCID: https://orcid.org/0000-0002-2874-8737)
- Michael C. Ostrowski (ORCID: https://orcid.org/0000-0003-2948-6297)
- Sudarshana M. Sharma (ORCID: https://orcid.org/0000-0002-9745-0061)
- Stefano Berto (ORCID: https://orcid.org/0000-0001-9028-9458)
- Jingxin Wang (ORCID: https://orcid.org/0000-0003-4036-2789)
- Teresa A. Zimmers (ORCID: https://orcid.org/0000-0001-7872-0540)
- Lauren B. Tolliver
- Benjamin R. Pryce (ORCID: https://orcid.org/0000-0002-1671-0918)
- Anna Crawford (ORCID: https://orcid.org/0000-0002-3151-8166)
- Eliza W. Beal (ORCID: https://orcid.org/0000-0003-2191-6811)
- Kübra Çalışır (ORCID: https://orcid.org/0000-0002-6204-1022)
- Denis C. Guttridge (ORCID: https://orcid.org/0000-0002-7276-6609)
- Bradley V. Watts (ORCID: https://orcid.org/0000-0003-2397-6359)
- Martin J. Romeo (ORCID: https://orcid.org/0000-0001-7941-1862)
- Victoria Spadafora
- Suganya Subramanian (ORCID: https://orcid.org/0009-0007-2822-9420)
- Noam Koren (ORCID: https://orcid.org/0000-0003-3269-6404)
- William P. Lancaster
- Morgan Overstreet
Institutions
- University of Iowa (US)
- Medical University of South Carolina (US)
- University of California, Los Angeles (US)
- Oregon Health & Science University (US)
- MUSC Hollings Cancer Center (US)
Publication Details
- Journal
- Cell Reports
- Published
- 2024-10-31
- DOI
- https://doi.org/10.1016/j.celrep.2024.114925
- Citations
- 36
- Primary Topic
- Nutrition and Health in Aging
- Type
- article
- Field-Weighted Citation Impact
- 11.76
Funders
- U.S. Department of Veterans Affairs
- Ohio State University
- Medical University of South Carolina
- National Institutes of Health
- Hollings Cancer Center, Medical University of South Carolina
- National Cancer Institute
- National Institute of Arthritis and Musculoskeletal and Skin Diseases