TREM2 alters the phagocytic, apoptotic and inflammatory response to Aβ42 in HMC3 cells

Akhter, Rumana; Shao, Yvonne; Formica, Shane; Khrestian, Maria; Bekris, Lynn M.

doi:10.1016/j.molimm.2020.12.035

Cited by 32 publications

(23 citation statements)

References 67 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…This disparity in morphology is evident across every in vitro culture model (Table 1 ). Commercially available human microglial cells lines SV40 and HMC3 have a varied morphology of globular and spindle-shaped cells with short processes and a few primary branches that fuse together when confluence is reached (Akhter et al 2021 ; Chiavari et al 2019 ; Dello Russo et al 2018 ) (Fig. 1 c).…”

Section: Comprehensive Overview: Model Description and Comparisonmentioning

confidence: 99%

Human microglial models to study HIV infection and neuropathogenesis: a literature overview and comparative analyses

et al. 2022

View full text Add to dashboard Cite

HIV persistence in the CNS despite antiretroviral therapy may cause neurological disorders and poses a critical challenge for HIV cure. Understanding the pathobiology of HIV-infected microglia, the main viral CNS reservoir, is imperative. Here, we provide a comprehensive comparison of human microglial culture models: cultured primary microglia (pMG), microglial cell lines, monocyte-derived microglia (MDMi), stem cell–derived microglia (iPSC-MG), and microglia grown in 3D cerebral organoids (oMG) as potential model systems to advance HIV research on microglia. Functional characterization revealed phagocytic capabilities and responsiveness to LPS across all models. Microglial transcriptome profiles of uncultured pMG showed the highest similarity to cultured pMG and oMG, followed by iPSC-MG and then MDMi. Direct comparison of HIV infection showed a striking difference, with high levels of viral replication in cultured pMG and MDMi and relatively low levels in oMG resembling HIV infection observed in post-mortem biopsies, while the SV40 and HMC3 cell lines did not support HIV infection. Altogether, based on transcriptional similarities to uncultured pMG and susceptibility to HIV infection, MDMi may serve as a first screening tool, whereas oMG, cultured pMG, and iPSC-MG provide more representative microglial culture models for HIV research. The use of current human microglial cell lines (SV40, HMC3) is not recommended.

show abstract

Section: Comprehensive Overview: Model Description and Comparisonmentioning

confidence: 99%

Human microglial models to study HIV infection and neuropathogenesis: a literature overview and comparative analyses

et al. 2022

View full text Add to dashboard Cite

show abstract

“…Recently, triggering by receptor expressed on myeloid cell 2 (TREM2) was identified as regulator of both IP-10 and FGF-2 beside others. TREM2 is involved in the activation of IP-10, MIP-1a, and IL-8, while it inhibits FGF-2, and thus it plays a role in enhancing the microglial function, suggesting that therapeutic strategies that seek to activate TREM2 may not only enhance phagocytosis, but also inhibit apoptosis [ 43 ]. Taken together, this novel association between IP-10 as a marker influencing the post-aSAH outcome and FGF-2 suggests independent pathological pathways in the neuroinflammatory response after aSAH.…”

Section: Discussionmentioning

confidence: 99%

Biomarker Associations in Delayed Cerebral Ischemia after Aneurysmal Subarachnoid Hemorrhage

Spantler

Molnár

Simon

et al. 2022

IJMS

View full text Add to dashboard Cite

The prognosis for patients with aneurysmal subarachnoid hemorrhage (aSAH) is heavily influenced by the development of delayed cerebral ischemia (DCI), but the adequate and effective therapy of DCI to this day has not been resolved. Multiplex serum biomarker studies may help to understand the pathophysiological processes underlying DCI. Samples were collected from patients with aSAH at two time points: (1) 24 h (Day 1) and (2) 5–7 days after ictus. Serum concentrations of eotaxin, FGF-2, FLT-3L, CX3CL1, Il-1b, IL-4, IP-10, MCP3, and MIP-1b were determined using a customized MILLIPLEX Human Cytokine/Chemokine/Growth Factor Panel A multiplex assay. The functional outcome was defined by the modified Rankin scale (favorable: 0–2, unfavorable: 3–6) measured on the 30th day after aSAH. One-hundred and twelve patients with aSAH were included in this study. The median level of CX3CL1 and MCP-3 measured on Days 5–7 were significantly higher in patients with DCI compared with those without DCI (CX3CL1: with DCI: 110.5 pg/mL, IQR: 82–201 vs. without DCI: 82.6, 58–119, p = 0.036; and MCP-3: with DCI: 22 pg/mL (0–32) vs. without DCI: 0 (0–11), p < 0.001). IP-10, MCP-3, and MIP-1b also showed significant associations with the functional outcome after aSAH. MCP-3 and CX3CL1 may play a role in the pathophysiology of DCI.

show abstract

“…In one study, HMC3 cells appeared elongated and bipolar following stimulation with IFNγ+IL1β for 24 h [ 89 ]. In another report, activation with a high concentration of Aβ42 (5 µM) for 24 h corresponded to the acquisition of an amoeboid shape [ 90 ].…”

Section: Discussionmentioning

confidence: 99%

SIRT1-Dependent Upregulation of BDNF in Human Microglia Challenged with Aβ: An Early but Transient Response Rescued by Melatonin

et al. 2021

View full text Add to dashboard Cite

Microglia represent a first-line defense in the brain. However, in pathological conditions such as Alzheimer’s disease (AD), a pro-inflammatory switch may occur, leading to loss of protective functions. Using the human microglial cell line HMC3, we showed that exposure to low concentrations of β-amyloid peptide 1-42 (Aβ42; 0.2 μM) initially (6 h) upregulated anti-inflammatory markers interleukin (IL)-4, IL-13, and brain-derived neurotrophic factor (BDNF). BDNF increase was prevented by selective inhibition of SIRT1 with EX527 (2 μM). Accordingly, these early effects were accompanied by a significant Aβ42-induced increase of SIRT1 expression, nuclear localization, and activity. SIRT1 modulation involved adenosine monophosphate-regulated kinase (AMPK), which was promptly (30 min) phosphorylated by Aβ42, while the AMPK inhibitor BML-275 (2 μM) attenuated Aβ42-induced SIRT1 increase. Initially observed microglial responses appeared transient, as microglial features changed when exposure to Aβ42 was prolonged (0.2 μM for 72 h). While SIRT1 and BDNF levels were reduced, the expression of inflammatory markers IL-1β and tumor necrosis factor (TNF)-α increased. This coincided with a rise in NF-kB nuclear localization. The effects of melatonin (1 μM) on prolonged microglial exposure to Aβ42 were analyzed for their protective potential. Melatonin was able to prolong SIRT1 and BDNF upregulation, as well as to prevent NF-kB nuclear translocation and acetylation. These effects were sensitive to the melatonin receptor antagonist, luzindole (25 μM). In conclusion, our data define an early microglial defensive response to Aβ42, featuring SIRT1-mediated BDNF upregulation that can be exogenously modulated by melatonin, thus identifying an important target for neuroprotection.

show abstract

TREM2 alters the phagocytic, apoptotic and inflammatory response to Aβ42 in HMC3 cells

Cited by 32 publications

References 67 publications

Human microglial models to study HIV infection and neuropathogenesis: a literature overview and comparative analyses

Human microglial models to study HIV infection and neuropathogenesis: a literature overview and comparative analyses

Biomarker Associations in Delayed Cerebral Ischemia after Aneurysmal Subarachnoid Hemorrhage

SIRT1-Dependent Upregulation of BDNF in Human Microglia Challenged with Aβ: An Early but Transient Response Rescued by Melatonin

Contact Info

Product

Resources

About