The nuclear receptor Nur77 suppresses CNS autoimmunity by limiting myeloid catecholamine production (BA3P.134)

Abstract

Abstract In multiple sclerosis (MS) and its mouse model, experimental autoimmune encephalitis (EAE), recruitment of peripheral autoreactive leukocytes to the central nervous system (CNS) is central for pathogenesis. Although sympathetic norepinephrine (NE) has been described as a key driving force of leukocyte recruitment, molecular mechanisms that control this process have not been fully elucidated. Macrophages can also produce NE, but the importance of this activity has not been addressed in the MS context. Nur77, an orphan nuclear receptor involved in differentiation of monocytes, can be activated by both inflammatory and sympathetic stimuli. Here we show that in macrophages, Nur77 is essential to regulate expression of tyrosine hydroxylase (TH), a rate-limiting enzyme in catecholamine biosynthesis. Mice with global or myeloid-specific Nur77 deletion exhibited enhanced TH expression and elevated blood NE levels, which triggered excessive production of IL-6, CXCL1, CCL2 and CCL5, ultimately leading to accelerated and exacerbated EAE. Live cell imaging of the spinal cord revealed enhanced infiltration of encephalitogenic 2D2 T cells and monocytes, and hastened activation of microglia in Nur77-deficient mice. Consistently, exacerbated EAE in Nur77-deficient mice was ameliorated by TH inhibition or by α1 adrenergic receptor blockade. Our data identify Nur77 as a key nuclear receptor regulating myeloid catecholamine production and CNS autoimmunity.