TREM-1-dependent macrophage infiltration mediates visceral hypersensitivity via vlPAG GABAergic neuron activation in a mouse model of inflammatory bowel disease.

backgroundVisceral pain is a common symptom of inflammatory bowel disease (IBD). Although triggering receptor expressed on myeloid cells-1 (TREM-1) has been shown to induce infiltration of peripheral immune cells into the central nervous system, the specific contribution of peripheral monocytes/macrophages (Mo/MΦ) to visceral pain in IBD remains elusive. This study aimed to investigate the effect of TREM-1-dependent macrophage infiltration in the periaqueductal gray (PAG) on visceral pain and the underlying mechanisms in IBD.

methodsMale C57BL/6 J or Trem1

resultsPeripheral Mo/MΦ infiltration into the PAG played a dominant role in enhancing ventrolateral PAG (vlPAG) GABAergic neuronal activity in mice with acute colitis, compared with the relatively minor contributions of resident microglia and peripheral neutrophils. This promoted acute visceral pain during intestinal inflammation with visceral pain persisting into the remission phase. To validate the role of peripheral TREM-1-expressing Mo/MΦ in visceral pain, microinjection of Ly6C⁺ monocytes into the vlPAG led to activation of vlPAG GABAergic neurons and an increase in visceral pain sensitivity. Pharmacological inhibition and gene knockout of TREM-1 both reduced Mo/MΦ infiltration, leading to decreased vlPAG GABAergic neuronal activity and mitigatory visceral pain.

conclusionsOur study identifies peripheral Mo/MΦ TREM-1 as a mediator promoting visceral pain via vlPAG GABAergic neuron activation. This finding presents a promising therapeutic approach for treating acute intestinal inflammation and visceral pain in colitis, while also offering a potential target for managing chronic visceral pain that persists in patients with IBD.