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TREM2- and DAP12-dependent activation of PI3K requires DAP10 and is inhibited by SHIP1.

ABSTRACT: The activation and fusion of macrophages and of osteoclasts require the adaptor molecule DNAX-activating protein of 12 kD (DAP12), which contains immunoreceptor tyrosine-based activation motifs (ITAMs). TREM2 (triggering receptor expressed on myeloid cells-2) is the main DAP12-associated receptor in osteoclasts and, similar to DAP12 deficiency, loss of TREM2 in humans leads to Nasu-Hakola disease, which is characterized by bone cysts and dementia. Furthermore, in vitro experiments have shown that deficiency in DAP12 or TREM2 leads to impaired osteoclast development and the formation of mononuclear osteoclasts. Here, we demonstrate that the ligation of TREM2 activated phosphatidylinositol 3-kinase (PI3K), extracellular signal-regulated kinase 1 (ERK1) and ERK2, and the guanine nucleotide exchange factor Vav3; induced the mobilization of intracellular calcium (Ca(2+)) and the reorganization of actin; and prevented apoptosis. The signaling adaptor molecule DAP10 played a key role in the TREM2- and DAP12-dependent recruitment of PI3K to the signaling complex. Src homology 2 (SH2) domain-containing inositol phosphatase-1 (SHIP1) inhibited TREM2- and DAP12-induced signaling by binding to DAP12 in an SH2 domain-dependent manner and preventing the recruitment of PI3K to DAP12. These results demonstrate a previously uncharacterized interaction of SHIP1 with DAP12 that functionally limits TREM2- and DAP12-dependent signaling and identify a mechanism through which SHIP1 regulates key ITAM-containing receptors by directly blocking the binding and activation of PI3K.

SUBMITTER: Peng Q

PROVIDER: S-EPMC2900152 | biostudies-literature | 2010 May

REPOSITORIES: biostudies-literature

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TREM2- and DAP12-dependent activation of PI3K requires DAP10 and is inhibited by SHIP1.

Peng Qisheng Q Malhotra Shikha S Torchia James A JA Kerr William G WG Coggeshall K Mark KM Humphrey Mary Beth MB

Science signaling 20100518 122

The activation and fusion of macrophages and of osteoclasts require the adaptor molecule DNAX-activating protein of 12 kD (DAP12), which contains immunoreceptor tyrosine-based activation motifs (ITAMs). TREM2 (triggering receptor expressed on myeloid cells-2) is the main DAP12-associated receptor in osteoclasts and, similar to DAP12 deficiency, loss of TREM2 in humans leads to Nasu-Hakola disease, which is characterized by bone cysts and dementia. Furthermore, in vitro experiments have shown tha ...[more]

PMID: 20484116

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Project description:Neuropathic pain afflicts millions of people, and the development of an effective treatment for this intractable pain is an urgent issue. Recent evidence has implicated microglia in neuropathic pain. The present study showed that the DNAX-activating protein of 12 kDa (DAP12) and its associated "triggering receptor expressed on myeloid cells 2" (TREM2) were predominantly expressed by microglia in the dorsal horn after spinal nerve injury, revealing a role for TREM2/DAP12 signaling in neuropathic pain. Nerve injury-induced proinflammatory cytokine expression in microglia and pain behaviors were significantly suppressed in Dap12-deficient mice. Furthermore, intrathecal administration of TREM2 agonistic antibody induced proinflammatory cytokine expression, as well as neuropathic pain, in mice without nerve injury. The agonistic antibody induced proinflammatory responses and neuropathic pain was not observed in Dap12-deficient mice. Together, these results suggest that TREM2/DAP12-mediated signals in microglia exacerbate nerve injury-induced neuropathic pain by inducing proinflammatory cytokine secretion from microglia. Suppression of DAP12-mediated signals could be a therapeutic target for neuropathic pain. SIGNIFICANCE STATEMENT:Recent studies have revealed that activated microglia in the spinal dorsal horn exacerbate neuropathic pain, which has suggested that suppression of microglial activity should be considered as a therapeutic target. However, only a few molecules have been identified as regulators of microglial activity. In this study, we focused on a receptor complex of TREM2 and DAP12, both of which are expressed by microglia and have been implicated in the pathogenesis of Alzheimer's disease, and demonstrated that TREM2/DAP12 signaling promoted proinflammatory responses in microglia and exacerbates neuropathic pain. The present results revealed the functional significance of TREM2/DAP12 signaling in microglial activation after neuronal injury, and could help in the development of treatments for neuropathic pain and neurodegenerative diseases.

Project description:BACKGROUND:Neuroinflammation is an important host defense response to secondary brain injury after intracerebral hemorrhage (ICH). Triggering receptor expressed on myeloid cells 2 (TREM2) confers strong neuroprotective effects by attenuating neuroinflammation in experimental ischemic stroke. Recent studies suggest that apolipoprotein E (apoE) is a novel, high-affinity ligand of TREM2. This study aimed to investigate the effects of TREM2 activation on neuroinflammation and neuronal apoptosis in a mouse model of ICH. METHODS:Adult male CD1 mice (n = 216) were subjected to intrastriatal injection of bacterial collagenase. The TREM2 ligand, apoE-mimetic peptide COG1410 was administered intranasally at 1?h after ICH induction. To elucidate the underlying mechanism, TREM2 small interfering RNA (siRNA) and the phosphatidylinositol 3-kinase (PI3K) inhibitor LY294002 were administered intracerebroventricularly prior to COG1410 treatment. Neurobehavioral tests, brain water content, immunofluorescence, western blotting, and Fluoro-Jade C- and terminal deoxynucleotidyl transferase dUTP nick end labeling staining were performed. RESULTS:Endogenous TREM2 expression was increased and peaked at 24?h after ICH. TREM2 was expressed on microglia, astrocytes, and neurons. COG1410 improved both short-term and long-term neurological functions, reduced brain edema, inhibited microglia/macrophage activation and neutrophil infiltration, and suppressed neuronal apoptotic cell death in perihematomal areas after ICH. Knockdown of endogenous TREM2 by TREM2 siRNA aggravated neurological deficits and decreased the expression of TREM2 in naïve and ICH mice. COG1410 was associated with upregulation of TREM2, PI3K, phosphorylated-Akt, and Bcl-2 and downregulation of TNF-?, IL-1?, and Bax after ICH. The neuroprotective effects of COG1410 were abolished by both TREM2 siRNA and PI3K inhibitor LY294002. CONCLUSIONS:Our finding demonstrated that TREM2 activation improved neurological functions and attenuated neuroinflammation and neuronal apoptosis after ICH, which was, at least in part, mediated by activation of PI3K/Akt signaling pathway. Therefore, activation of TREM2 may be a potential therapeutic strategy for the management of ICH patients.

Dataset Information

TREM2- and DAP12-dependent activation of PI3K requires DAP10 and is inhibited by SHIP1.

Publications

TREM2- and DAP12-dependent activation of PI3K requires DAP10 and is inhibited by SHIP1.

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