Human Mas-related G protein-coupled receptors-X1 induce chemokine receptor 2 expression in rat dorsal root ganglia neurons and release of chemokine ligand 2 from the human LAD-2 mast cell line

Primate-specific Mas-related G protein-coupled receptors-X1
(MRGPR-X1) are highly enriched in dorsal root ganglia (DRG) neurons
and induce acute pain. Herein, we analyzed effects of MRGPR-X1 on
serum response factors (SRF) or nuclear factors of activated T
cells (NFAT), which control expression of various markers of
chronic pain. Using HEK293, DRG neuron-derived F11 cells and
cultured rat DRG neurons recombinantly expressing human MRGPR-X1,
we found activation of a SRF reporter gene construct and induction
of the early growth response protein-1 via extracellular
signal-regulated kinases-1/2 known to play a significant role in
the development of inflammatory pain. Furthermore, we observed
MRGPR-X1-induced up-regulation of the chemokine receptor 2 (CCR2)
via NFAT, which is considered as a key event in the onset of
neuropathic pain and, so far, has not yet been described for any
endogenous neuropeptide. Up-regulation of CCR2 is often associated
with increased release of its endogenous agonist chemokine ligand 2
(CCL2). We also found MRGPR-X1-promoted release of CCL2 in a human
connective tissue mast cell line endogenously expressing MRGPR-X1.
Thus, we provide first evidence to suggest that MRGPR-X1 induce
expression of chronic pain markers in DRG neurons and propose a so
far unidentified signaling circuit that enhances chemokine
signaling by acting on two distinct yet functionally co-operating
cell types. Given the important role of chemokine signaling in pain
chronification, we propose that interruption of this signaling
circuit might be a promising new strategy to alleviate
chemokine-promoted pain.