Disruption of a self-amplifying catecholamine loop reduces cytokine release syndrome
Open accessAbstract
Cytokine release syndrome (CRS) is a life-threatening complication of several new immunotherapies used to treat cancers and autoimmune diseases 1-5. Here we report that atrial natriuretic peptide can protect mice from CRS induced by such agents by reducing the levels of circulating catecholamines. Catecholamines were found to orchestrate an immunodysregulation resulting from oncolytic bacteria and lipopolysaccharide through a self-amplifying loop in macrophages. Myeloid-specific deletion of tyrosine hydroxylase inhibited this circuit. Cytokine release induced by T-cell-activating therapeutic agents was also accompanied by a catecholamine surge and inhibition of catecholamine synthesis reduced cytokine release in vitro and in mice. Pharmacologic catecholamine blockade with metyrosine protected mice from lethal complications of CRS resulting from infections and various biotherapeutic agents including oncolytic bacteria, T-cell-targeting antibodies and CAR-T cells. Our study identifies catecholamines as an essential component of the cytokine release that can be modulated by specific blockers without impairing the therapeutic response.
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Therapy for cytokine release syndrome and its neurological toxicity chiefly targets IL-6, which probably originates from monocytes or activated endothelial cells.
“Treatment for CRS and associated neurotoxicity primarily targets IL-6, likely arising from monocytes or activated endothelium [1, 6, 11–17].”
From Immune reconstitution and clinical recovery following anti-CD28 antibody (TGN1412)-induced cytokine storm (2021) · cites this paper as [15]
The paper reports testing IL-6 receptor blockade for CRS in mice, with a significant but marginal survival benefit, and identifies IL-6 among myeloid-derived cytokines (main text, labelled Abstract in our copy; page unavailable). It does not establish that treatment for CRS and associated neurotoxicity primarily targets IL-6, or that activated endothelium is a likely source of IL-6. (LLM, conf=0.84)
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References 49 · Cited by 277
- Authors
- Staedtke, V., Bai, R.-Y., Kim, K., Darvas, M., Davila, M. L., Riggins, G. J., Rothman, P. B., Papadopoulos, N., Kinzler, K. W., Vogelstein, B., & Zhou, S.
- Affiliations
- Howard Hughes Medical Institute (US)
- Johns Hopkins University (US)
- University of Washington (US)
- Moffitt Cancer Center (US)
- Corresponding author
- Staedtke, Verena
- Bai, Ren-Yuan
- Vogelstein, Bert
- Zhou, Shibin
- ORCID
- Venue
- Nature
- Published
- 2018-12-12
- Volume
- 564
- Issue
- 7735
- Pages
- 273-277
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- PMC
- PMC6512810
- OpenAlex
- W2903675281
- Cited by
- 277
- References
- 49
- Citations by year
- 2026: 23 · 2025: 22 · 2024: 33 · 2023: 37 · 2022: 44 · 2021: 53 · 2020: 52 · 2019: 12 · 2018: 1
- FWCI
- 11.07
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- Funders
- National Cancer Institute (K08CA230179, R03CA178118, P50CA062924, K12CA090625, U54CA196519)
- National Institute of Neurological Disorders and Stroke (R25NS065729)
- Topics
- Health Sciences › Medicine › Oncology › Cancer Immunotherapy and Biomarkers
- Life Sciences › Immunology and Microbiology › Immunology › Immunotherapy and Immune Responses
- Life Sciences › Immunology and Microbiology › Immunology › Immunotoxicology and immune responses
- Keywords
- cytokine release syndrome, catecholamines, atrial natriuretic peptide, tyrosine hydroxylase, macrophages, oncolytic bacteria, lipopolysaccharide, chimeric antigen receptor T cells, alpha-methyl-p-tyrosine, immunotherapy toxicity, immune dysregulation, anti-inflammatory peptides
- MeSH terms
- Animals, Catecholamines, Epinephrine, Female, Humans, Male, Mice, Inbred BALB C, Mice, Inbred C57BL, Atrial Natriuretic Factor, Norepinephrine, Receptors, Antigen, T-Cell, Syndrome, T-Lymphocytes, Cytokines, Immunotherapy, Adoptive, CD3 Complex, alpha-Methyltyrosine, Myeloid Cells, Mice, Kaplan-Meier Estimate, In Vitro Techniques
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