Macrophages, Monocytes Amplify Neuroinflammation in Multiple Sclerosis

Long thought to be driven by T cells, a mouse model indicates a troublesome role for macrophages in MS.

Transcription factor Nr4a1, which regulates the production of norepinephine in macrophages, may be a good target for multiple sclerosis treatment, a mouse model suggests.  

Study data, published in Nature Immunology, indicates a previously unknown role for macrophages in neuroinflammation.

“Although multiple sclerosis (MS) is generally considered a T cell-driven disease, many studies have shown that monocytes and monocyte-derived macrophages are also crucial for the development of MS,” Catherine C. Hedrick, PhD, of the Division of Inflammation Biology at La Jolla Institute for Allergy and Immunology in La Jolla, CA told Neurology Advisor.  “It is increasingly clear that macrophages recruited in response to inflammation are fundamentally different from homeostatic local microglia within the CNS, and therefore should get special attention for their relevance in initiation and progression of CNS autoimmunity.”

CLINICAL CHART: Multiple Sclerosis Treatments

Hedrick and colleagues hypothesized that Nr4a1 may be involved in the interaction of the immune system and sympathetic nervous system in the setting of neuroinflammation. Norepinephrine has previously been shown to play a role in experimental autoimmune encephalitis (EAE), the rodent model of MS. Using an established passive rodent module of EAE to better understand the role of Nr4a1 in CNS autoimmunity, the investigators conducted a series of experiments, including intravital microscopy to observe CNS damage and leukocyte infiltration, flow cytometry to look at the expression of tyrosine hydroxylase (TH), and a mouse macrophage cell line to understand Nr4a1’s regulation of TH.

The investigators found that Nr4a1 was involved in regulating the production of norepinephrine within macrophages which limited the development of EAE in the rodent model. Furthermore, mice without Nr4a1 developed EAE at an accelerated pace and produced higher levels of interleukin 6, norepinephrine, and early T cell infiltration in the CNS. They also demonstrated that Nr4a1 is involved in the inhibition of expression of TH in macrophages; when TH was deleted, the rodent models were protected from EAE.

“Monocytes and macrophages can respond to and produce not only inflammatory but also neuronal mediators, which confers them a vital role in brain to immune communication,” Dr. Hedrick said.

“Human monocytes and derived macrophages undergo changes in response to both inflammatory and neuronal cues which turns them in to an attractive candidate in the diagnosis and treatment of multiple sclerosis as well as other neuroinflammatory conditions,” Dr. Hedrick continued. “Specifically targeting catecholamine-producing macrophages, recruited to the CNS, may inhibit neuroinflammation.”


  1. Shaked I, Hanna RN, Shaked H, et al. Transcription factor Nr4a1 couples sympathetic and inflammatory cues in CNS-recruited macrophages to limit neuroinflammation. Nat Immunol. 2015; doi:10.1038/ni.3321.