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

BACKGROUND: Visceral 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. METHODS: mice were fed 2% dextran sodium sulfate (DSS) for 7 days to induce colitis. Flow sorting, flow cytometry, and western blot were employed to isolate, transfer, and detect immune cells as well as TREM-1 expression. Immunofluorescence and in vitro brain slice electrophysiology were used to assess the activity of GABAergic neurons. Visceral pain was evaluated using the abdominal withdrawal reflex (AWR) score, visceral pain threshold, and electromyography (EMG). RESULTS: Peripheral 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. CONCLUSIONS: Our 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.