The microglial innate immune receptors TREM-1 and TREM-2 in the anterior cingulate cortex (ACC) drive visceral hypersensitivity and depressive-like behaviors following DSS-induced colitis

• Published in: Brain, behavior, and immunity Vol. 112; pp. 96 - 117
• Main Authors: Wu, Ke, Liu, Yue-ying, Shao, Shuai, Song, Wei, Chen, Xing-han, Dong, Yu-ting, Zhang, Yong-mei
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier Inc 01.08.2023
• Subjects: Anterior cingulate cortex; Colitis; Depression; Gyrus Cinguli; Humans; Immunity, Innate; Inflammation; Inflammatory bowel disease; Inflammatory Bowel Diseases; Microglia; Microglia - metabolism; TREM-1; TREM-2; Triggering Receptor Expressed on Myeloid Cells-1 - metabolism; Visceral hypersensitivity; dCA1; DG; EPM; DAP12; mEPSC; SPF; PVN; UC; AUC; PRR; TLT-1/2; r/t; SPT; FITC-dextran; EMG; TREM-1/2; IL; SDS; DSS; FST; H&E; PAGE; EP; SYP; IL-1β; IL-6; Microglia; Inflammatory bowel disease; TREM-2; TREM-1; mPFC; CRD; TST; NC; PMSF; Visceral hypersensitivity; CRH; GABA; VTA; CNO; CNS; IBD; MFI; ANOVA; Mino; TTX; AWR; OFT; PLX; WT; VHS; Acb; ACC; CD; DNAX; KO; Anterior cingulate cortex; TBST; Depression; siRNA; ACSF; PrL; DAI; PMN; PSD95; TNF-α; PAG; VMR
• ISSN: 0889-1591; 1090-2139
• DOI: 10.1016/j.bbi.2023.06.003

•DSS-induced colitis provokes ACCGlu neuronal activation, resulting in persistent visceral hypersensitivity.•The dual nature of microglia in ACC modulates visceral hypersensitivity and depressive-like behaviors following colitis.•TREM-1 deficiency blocks increased microglia activity and attenuates visceral hypersensitivity in the inflammatory phase.•TREM-2 deficiency decreases the phagocytosis of microglia and prevents the emergence of depression in the remission phase. Inflammatory bowel disease (IBD) is a chronic condition with a high recurrence rate. To date, the clinical treatment of IBD mainly focuses on inflammation and gastrointestinal symptoms while ignoring the accompanying visceral pain, anxiety, depression, and other emotional symptoms. Evidence is accumulating that bi-directional communication between the gut and the brain is indispensable in the pathophysiology of IBD and its comorbidities. Increasing efforts have been focused on elucidating the central immune mechanisms in visceral hypersensitivity and depression following colitis. The triggering receptors expressed on myeloid cells-1/2 (TREM-1/2) are newly identified receptors that can be expressed on microglia. In particular, TREM-1 acts as an immune and inflammatory response amplifier, while TREM-2 may function as a molecule with a putative antagonist role to TREM-1. In the present study, using the dextran sulfate sodium (DSS)-induced colitis model, we found that peripheral inflammation induced microglial and glutamatergic neuronal activation in the anterior cingulate cortex (ACC). Microglial ablation mitigated visceral hypersensitivity in the inflammation phase rather than in the remission phase, subsequently preventing the emergence of depressive-like behaviors in the remission phase. Moreover, a further mechanistic study revealed that overexpression of TREM-1 and TREM-2 remarkably aggravated DSS-induced neuropathology. The improved outcome was achieved by modifying the balance of TREM-1 and TREM-2 via genetic and pharmacological means. Specifically, a deficiency of TREM-1 attenuated visceral hyperpathia in the inflammatory phase, and a TREM-2 deficiency improved depression-like symptoms in the remission phase. Taken together, our findings provide insights into mechanism-based therapy for inflammatory disorders and establish that microglial innate immune receptors TREM-1 and TREM-2 may represent a therapeutic target for the treatment of pain and psychological comorbidities associated with chronic inflammatory diseases by modulating neuroinflammatory responses.