TREM2/β-catenin attenuates NLRP3 inflammasome-mediated macrophage pyroptosis to promote bacterial clearance of pyogenic bacteria

Abstract

Triggering receptors expressed on myeloid cells 2 (TREM2) is considered a protective factor to protect host from bacterial infection, while how it elicits this role is unclear. In the present study, we demonstrate that deficiency of triggering receptors expressed on myeloid cells 2 (TREM2) significantly enhanced macrophage pyroptosis induced by four common pyogenic bacteria including Staphylococcus aureus, Pseudomonas aeruginosa, Streptococcus pneumoniae, and Escherichia coli. TREM2 deficiency also decreased bacterial killing ratio of macrophage, while Caspase-1 or GSDMD inhibition promoted macrophage-mediated clearance to these bacteria. Further study demonstrated that the effect of TREM2 on macrophage pyroptosis and bacterial eradication mainly dependents on the activated status of NLRP3 inflammasome. Moreover, as the key downstream of TREM2, β-catenin phosphorylated at Ser675 by TREM2 signal and accumulated in nucleus and cytoplasm. β-catenin mediated the effect of TREM2 on NLRP3 inflammasome and macrophage pyroptosis by reducing NLRP3 expression, and inhibiting inflammasome complex assembly by interacting with ASC. Collectively, TREM2/β-catenin inhibits NLRP3 inflammasome to regulate macrophage pyroptosis, and enhances macrophage-mediated pyogenic bacterial clearance.

Photothermal Controlled‐Release Immunomodulatory Nanoplatform for Restoring Nerve Structure and Mechanical Nociception in Infectious Diabetic Ulcers

“…Trem2 + macrophages promote bacterial clearance, collagen remodeling, and full-thickness skin regeneration during wound healing. [28,63] Here, it was demonstrated that the recruitment of Trem2 + macrophages on Day 3 was statistically higher in the pGel/M-NIR and MpGel-NIR groups, and the MpGel-NIR group maintained this increase on Day 28, indicating the beneficial recruitment of macrophages by pGO. (Figure 5A,B,E,F and Figure S13, Supporting Information).…”

Breviscapine alleviates podocyte injury by inhibiting NF-κB/NLRP3-mediated pyroptosis in diabetic nephropathy

“…The role of NLRP3-mediated pyroptosis in podocyte injury was next investigated using MCC950 (NLRP3 inhibitor) ( Tang et al, 2020 ), Ac-YVAD-CMK (caspase-1 inhibitor) ( Wang et al, 2022b ), and nigericin (NLRP3 activator) ( Jian et al, 2020 ; Mo et al, 2021 ). Podocytes were treated with HG in the presence or absence of MCC950, Ac-YVAD-CMK, or nigericin, and then podocyte injury was evaluated.…”

Proximity Proteome Analysis Reveals Novel TREM2 Interactors in the ER-Mitochondria Interface of Human Microglia

“…MERC is shown to serve as a signaling hub for NLRP3 inflammasome activation (Horng et al, 2014; Zhou et al, 2020). TREM2 is a direct regulator of the NLRP3 inflammasome and the AD-linked R47H TREM2 variant is not capable of activating the inflammasome (Cosker et al, 2021; Li et al, 2021; Jiang et al, 2022; Wang et al, 2022). These observations further substantiate the idea of the central role for TREM2 in regulating MERC functions.…”

“…ITPRIP gene (The gene encoding inositol 1,4,5trisphosphate receptor interacting protein) has also been suggested as an AD risk gene (Simino et al, 2017). AUP1 and REEP5 are known to play a key role in LD biogenesis (Robichaud et al, 2021;Chen et al, 2022), consistent with the functional role for TREM2 in the LD biogenesis. Collectively, our current study provides new insights on TREM2 functions and serves as a foundation for further research aimed at deciphering new molecular players in microglial TREM2 functions.…”