Key Points
Neutrophils constitutively express the histamine-synthesizing enzyme HDC.
Regardless of its source, histamine does not contribute to EAE.
Neutrophil-derived histamine contributes to IgE-mediated anaphylaxis.
Abstract
Histamine is best known for its role in allergies, but it could also be involved in autoimmune diseases such as multiple sclerosis. However, studies using experimental autoimmune encephalomyelitis (EAE), the most widely used animal model for multiple sclerosis, have reported conflicting observations and suggest the implication of a nonclassical source of histamine. In this study, we demonstrate that neutrophils are the main producers of histamine in the spinal cord of EAE mice. To assess the role of histamine by taking into account its different cellular sources, we used CRISPR–Cas9 to generate conditional knockout mice for the histamine-synthesizing enzyme histidine decarboxylase. We found that ubiquitous and cell-specific deletions do not affect the course of EAE. However, neutrophil-specific deletion attenuates hypothermia caused by IgE-mediated anaphylaxis, whereas neuron-specific deletion reduces circadian activity. In summary, this study refutes the role of histamine in EAE, unveils a role for neutrophil-derived histamine in IgE-mediated anaphylaxis, and establishes a new mouse model to re-explore the inflammatory and neurologic roles of histamine.
Footnotes
This work was supported by grants to L.V. from the Multiple Sclerosis Society of Canada (3476), the Canadian Institutes for Health Research Institute of Neurosciences, Mental Health and Addiction (400154), and the Natural Sciences and Engineering Research Council of Canada (2015-05073).
The online version of this article contains supplemental material.
- Received June 17, 2020.
- Accepted March 1, 2021.
- Copyright © 2021 by The American Association of Immunologists, Inc.