Disruption of a self-amplifying catecholamine loop reduces cytokine release syndrome

Nature. 2018 Dec;564(7735):273-277. doi: 10.1038/s41586-018-0774-y. Epub 2018 Dec 12.


Cytokine release syndrome (CRS) is a life-threatening complication of several new immunotherapies used to treat cancers and autoimmune diseases1-5. 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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Atrial Natriuretic Factor / pharmacology
  • CD3 Complex / antagonists & inhibitors
  • Catecholamines / antagonists & inhibitors*
  • Catecholamines / biosynthesis
  • Catecholamines / metabolism*
  • Cytokines / adverse effects*
  • Cytokines / immunology
  • Epinephrine / metabolism
  • Female
  • Humans
  • Immunotherapy, Adoptive
  • In Vitro Techniques
  • Kaplan-Meier Estimate
  • Male
  • Mice
  • Mice, Inbred BALB C
  • Mice, Inbred C57BL
  • Myeloid Cells / drug effects
  • Myeloid Cells / metabolism
  • Norepinephrine / metabolism
  • Receptors, Antigen, T-Cell / genetics
  • Receptors, Antigen, T-Cell / metabolism
  • Receptors, Antigen, T-Cell / therapeutic use
  • Syndrome*
  • T-Lymphocytes / drug effects
  • T-Lymphocytes / immunology
  • T-Lymphocytes / metabolism
  • alpha-Methyltyrosine / pharmacology


  • CD3 Complex
  • CTL019 chimeric antigen receptor
  • Catecholamines
  • Cytokines
  • Receptors, Antigen, T-Cell
  • alpha-Methyltyrosine
  • Atrial Natriuretic Factor
  • Norepinephrine
  • Epinephrine