Background
NR4A1, an orphan nuclear receptor, has been implicated in several biological events such as metabolism, apoptosis, and inflammation. Recent studies indicate a potential role for NR4A1in mast cells, yet its role in allergic responses remains largely unknown.

Objectives
The aim of this study was to clarify the role of NR4A1in mast cell activation and anaphylaxis.

Methods
To evaluate the function of NR4A1in mast cells, the impacts of siRNA knockdown, gene knockout, adenoviral overexpression, and pharmacological inhibition of NR4A1on FceRI signaling and effector functions in mouse bone marrow-derived mast cells (BMMCs) in vitro and on anaphylactic responses in vivo were evaluated.

Results
Knockdown or knockout of NR4A1 markedly suppressed degranulation and lipid mediator production by FceRI-crosslinked BMMCs, while its overexpression augmented these responses. Treatment with a NR4A1 antagonist also blocked mast cell activation to a similar extent as NR4A1 knockdown or knockout. Moreover, mast cell-specific NR4A1-deficient mice displayed dampened anaphylactic responses in vivo. Mechanistically, NR4A1 promoted FceRI signaling by counteracting the liver kinase B1 (LKB1)/AMP-activated protein kinase (AMPK) axis. Following FceRI crosslinking, NR4A1 bound to the LKB1/AMPK complex and sequestered it in the nucleus, thereby promoting FceRI downstream signaling pathways. Silencing or knockout of LKB1/AMPK largely abrogated the effect of NR4A1 on mast cell activation. Additionally, NR4A1 facilitated Syk activation independently of LKB1/AMPK.

Conclusions
NR4A1 positively regulates mast cell activation by antagonizing the LKB1-AMPK-dependent negative regulatory axis. This finding may provide a novel therapeutic strategy for the development of anti-allergic compounds.

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