Microglial Responses to Brain Injury and Disease: Functional Diversity and New Opportunities

Lyu, Junxuan; Jiang, Xiaoyan; Leak, Rehana K.; Shi, Yejie; Hu, Xiaoming; Chen, Jun

doi:10.1007/s12975-020-00857-2

Cited by 45 publications

(47 citation statements)

References 220 publications

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“…On the other hand, emerging evidence has demonstrated that inflammatory responses also play a beneficial role, and anti-inflammation is also one of the present neuroprotective agents’ main mechanisms. Activated microglia/macrophages can induce phagocytosis and the production of anti-inflammatory cytokines, which inhibits neuroinflammation and protects remaining viable neurons from death [ 9 – 12 ].…”

Section: Introductionmentioning

confidence: 99%

Activation of GPR39 with TC-G 1008 attenuates neuroinflammation via SIRT1/PGC-1α/Nrf2 pathway post-neonatal hypoxic–ischemic injury in rats

Xie

Jiang

Doycheva

et al. 2021

J Neuroinflammation

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Background Hypoxic–ischemic encephalopathy (HIE) is a severe anoxic brain injury that leads to premature mortality or long-term disabilities in infants. Neuroinflammation is a vital contributor to the pathogenic cascade post-HIE and a mediator to secondary neuronal death. As a plasma membrane G-protein-coupled receptor, GPR39, exhibits anti-inflammatory activity in several diseases. This study aimed to explore the neuroprotective function of GPR39 through inhibition of inflammation post-hypoxic–ischemic (HI) injury and to elaborate the contribution of sirtuin 1(SIRT1)/peroxisome proliferator-activated receptor-γ coactivator 1α (PGC-1α)/nuclear factor, erythroid 2 like 2(Nrf2) in G-protein-coupled receptor 39 (GPR39)-mediated protection. Methods A total of 206 10-day-old Sprague Dawley rat pups were subjected to HIE or sham surgery. TC-G 1008 was administered intranasally at 1 h, 25 h, 49 h, and 73 h post-HIE induction. SIRT1 inhibitor EX527, GPR39 CRISPR, and PGC-1α CRISPR were administered to elucidate the underlying mechanisms. Brain infarct area, short-term and long-term neurobehavioral tests, Nissl staining, western blot, and immunofluorescence staining were performed post-HIE. Results The expression of GPR39 and pathway-related proteins, SIRT1, PGC-1α and Nrf2 were increased in a time-dependent manner, peaking at 24 h or 48-h post-HIE. Intranasal administration of TC-G 1008 reduced the percent infarcted area and improved short-term and long-term neurological deficits. Moreover, TC-G 1008 treatment significantly increased the expression of SIRT1, PGC-1α and Nrf2, but downregulated the expressions of IL-6, IL-1β, and TNF-α. GPR39 CRISPR EX527 and PGC-1α CRISPR abolished GPR39’s neuroprotective effects post-HIE. Conclusions TC-G 1008 attenuated neuroinflammation in part via the SIRT1/PGC-1α/Nrf2 pathway in a neonatal rat model of HIE. TC-G 1008 may be a novel therapeutic target for treatment post-neonatal HIE injury.

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Section: Introductionmentioning

confidence: 99%

Activation of GPR39 with TC-G 1008 attenuates neuroinflammation via SIRT1/PGC-1α/Nrf2 pathway post-neonatal hypoxic–ischemic injury in rats

Xie

Jiang

Doycheva

et al. 2021

J Neuroinflammation

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show abstract

“…In contrast, Iba-1-positive microglial cells are responsible for the elimination of severely damaged or dead cells and for phagocytizing cell debris and xenogenic cells (23,(31)(32)(33). When exogenous cells are injected into the brain, many quiescent microglial cells can be reactivated (23,34,35), but they only phagocytize the identified heterogeneous cells.…”

Section: Discussionmentioning

confidence: 99%

Immunological Responses to Transgene-Modified Neural Stem Cells After Transplantation

Wei

Sun

et al. 2021

Front. Immunol.

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Neural stem cell (NSC) therapy is a promising therapeutic strategy for stroke. Researchers have frequently carried out genetic modification or gene editing of stem cells to improve survival or therapeutic function. However, NSC transplantation carries the risk of immune rejection, and genetic modification or gene-editing might further increase this risk. For instance, recent studies have reported on manipulating the stem cell genome and transplantation via the insertion of an exogenous gene derived from magnetotactic bacteria. However, whether transgene-modified stem cells are capable of inducing immunological reactions has not been explored. Although NSCs rarely express the major histocompatibility complex (MHC), they can still cause some immunological issues. To investigate whether transgene-modified NSCs aggravate immunological responses, we detected the changes in peripheral immune organs and intracerebral astrocytes, glial cells, and MHC-I and MHC-II molecules after the injection of GFP-labeled or mms6-GFP-labeled NSCs in a rat model. Xenogeneic human embryonic kidney (HEK-293T) cells were grafted as a positive control group. Our results indicated that xenogeneic cell transplantation resulted in a strong peripheral splenic response, increased astrocytes, enhanced microglial responses, and upregulation of MHC-I and MHC-II expression on the third day of transplantation. But they decreased obviously except Iba-1 positive cells and MHC-II expression. When injection of both mms6-GFP-labeled NSCs and GFP-labeled NSCs also induced similar responses as HEK-293T cells on the third days, but MHC-I and MHC-II expression decreased 3 weeks after transplantation. In addition, mms6 transgene-modified NSCs did not produce peripheral splenic response responses as well as astrocytes, microglial cells, MHC-I and MHC-II positive cells responses when compared with non-modified NSCs. The present study provides preliminary evidence that transgenic modification does not aggravate immunological responses in NSC transplantation.

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“…Toll-like receptor 4 ( TLR4 ) and triggering receptor expressed on myeloid cells 2 ( TREM2 ) are considered the main receptors to induce a pro-inflammatory and anti-inflammatory phenotype, respectively ( Zhou J. et al, 2019 ; Lyu et al, 2020 ). After SAH onset, the activated TLR4 can immediately recruit the special adaptor elements to induce downstream transduction signals, such as nuclear factor-κB (NF-κB) and mitogen-activated protein kinases (MAPKs) ( Akamatsu et al, 2019 ).…”

Section: Introductionmentioning

confidence: 99%

TREM2, Driving the Microglial Polarization, Has a TLR4 Sensitivity Profile After Subarachnoid Hemorrhage

Wang

et al. 2021

Front. Cell Dev. Biol.

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Increasing evidence suggests that triggering receptor expressed on myeloid cells 2 (TREM2) is implicated in the pathophysiology of neuroinflammation. The aim here was to investigate the neuroprotective role of TREM2 and its regulatory mechanism after subarachnoid hemorrhage (SAH). TREM2 siRNA was administered to measure the detrimental role of TREM2 in mediating microglial polarization in vivo and in vitro after experimental SAH. The relationship between Toll-like receptor 4 (TLR4) signaling and TREM2 was further explored. The soluble TREM2 from the cerebrospinal fluid (CSF) of patients with SAH was detected. The results showed that TREM2 mainly located in the microglia and presented a markedly delayed elevation after SAH. TREM2 knockdown triggered increased pro-inflammatory productions, aggravated microglial activities, and further exacerbated neurological dysfunction after SAH. Significantly, TLR4 knockout increased the expression of TREM2, accompanied by ameliorated neuroinflammation and improved neurological function. Corresponding to different clinical Hunt–Hess grades, obviously enhanced accumulation of soluble TREM2 was detected in the CSF of patients with SAH. TREM2 played a pivotal role in mediating microglial polarization after SAH, and the neuroprotective effect of TREM2 might be potentially suppressed by the hyperactive TLR4 in the early phase of SAH. Pharmacological targeting of TREM2 may be a promising strategy for SAH therapy.

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Microglial Responses to Brain Injury and Disease: Functional Diversity and New Opportunities

Cited by 45 publications

References 220 publications

Activation of GPR39 with TC-G 1008 attenuates neuroinflammation via SIRT1/PGC-1α/Nrf2 pathway post-neonatal hypoxic–ischemic injury in rats

Activation of GPR39 with TC-G 1008 attenuates neuroinflammation via SIRT1/PGC-1α/Nrf2 pathway post-neonatal hypoxic–ischemic injury in rats

Immunological Responses to Transgene-Modified Neural Stem Cells After Transplantation

TREM2, Driving the Microglial Polarization, Has a TLR4 Sensitivity Profile After Subarachnoid Hemorrhage

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