Wednesday, November 4, 2015

MΦ-specific catecholamine biosynthesis sustains neuroinflammation

A few weeks ago I reviewed new Science paper describing role of Nr4a1-positive monocytes in patrolling melanoma metastasis in the lungs. Now, the same research group has published another paper in Nature Immunology describing role of Nr4a1-positive macrophages (MΦ) in mouse model of neuroinflammation [EAE] that mimics human relapsing-remitting multiple sclerosis (RRMS).

Here, the authors have used the same Nr4a1-GFP mice to monitor its cellular expression during donor [2D2]-T cells induced EAE. Flow cytometric analysis revealed that CNS infiltrating MΦ expressed high level of GFP (i.e. Nr4a1). Of note, in their Science paper the same people mentioned that "Nr4a1 expression in macrophages and Ly6C+ monocytes is relatively low suggesting limited Nr4a1 function". It appears the authors are contradicted themselves from one to another paper.

Next, the authors showed that myeloid-specific deletion of Nr4a1 exaggerated EAE clinical scores.

The authors found, that mechanistically, exaggerated neuroinflammation seen in Nr4a1-deficient mice was [partially] related to MΦ-specific catecholamine production (summary of α1 adrenergic receptor inhibition, catecholamine depletion by 6-OHDA, and MΦ-specific tyrosine hydroxylase (ThΔLysm) deficiency). 

In summary, these results suggest that Nr4a1 orphan receptor influences catecholamine biosynthesis in MΦ and that inhibition of catecholamine [epinephrine, norepinephrine, and dopamine] production could benefit RRMS patients. While results with ThΔLysm mice reached statistical significance, more complete deletion of Th enzyme in ThΔCsfr1 or ThΔNr4a1 mice [as in Figure 2] would have provided better and cleaner view of the role of MΦ-specific catecholamine production on neuroinflammation.

David Usharauli

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