Effects of FGF2/FGFR1 Pathway on Expression of A1 Astrocytes After Infrasound Exposure

Zou, Lin-Hui; Shi, Yajun; He, Hua; Jiang, Shimei; Huo, Fang-Fang; Wang, Xiaomu; Wu, Fan; Ma, Lei

doi:10.3389/fnins.2019.00429

Cited by 27 publications

(24 citation statements)

References 20 publications

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“…Although CXCR7 small interfering RNA or CXCR7 knockout animals can be considered to further confirm the function of CXCR7 as the downstream mediator in microglia, our results suggest that there may be other mechanisms involved in the induction of A1 astrocytes by microglia. For example, Zou et al demonstrated that the inhibition of the fibroblast growth factor 2/fibroblast growth factor 2, receptor 1 (FGF2/FGFR1) pathway resulted in an increase in A1 astrocytes after infrasound damage [58]. Therefore, there are other receptors and signaling pathways related to the unbalanced polarization of astrocytes toward the A1 phenotype in the development of CPSP, which requires further study.…”

Section: Discussionmentioning

confidence: 99%

Microglia induce the transformation of A1/A2 reactive astrocytes via the CXCR7/PI3K/Akt pathway in chronic post-surgical pain

Liu

Chen

et al. 2020

J Neuroinflammation

128

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Background: Activated astrocytes play important roles in chronic post-surgical pain (CPSP). Recent studies have shown reactive astrocytes are classified into A1 and A2 phenotypes, but their precise roles in CPSP remain unknown. In this study, we investigated the roles of spinal cord A1 and A2 astrocytes and related mechanisms in CPSP. Methods: We used a skin/muscle incision and retraction (SMIR) model to establish a rat CPSP model. Microglia, CXCR7, and the phosphoinositide 3-kinase/Akt (PI3K/Akt) signaling pathways were regulated by intrathecal injections of minocycline (a non-specific microglial inhibitor), AMD3100 (a CXCR7 agonist), and LY294002 (a specific PI3K inhibitor), respectively. Mechanical allodynia was detected with von Frey filaments. The changes in microglia, A1 astrocytes, A2 astrocytes, CXCR7, and PI3K/Akt signaling pathways were examined by enzyme-linked immunosorbent assay (ELISA), western blot, and immunofluorescence. Results: Microglia were found to be activated, with an increase in interleukin-1 alpha (IL-1α), tumor necrosis factor alpha (TNFα), and complement component 1q (C1q) in the spinal cord at an early stage after SMIR. On day 14 after SMIR, spinal cord astrocytes were also activated; these were mainly of the A1 phenotype and less of the A2 phenotype. Intrathecal injection of minocycline relieved SMIR-induced mechanical allodynia and reverted the ratio of A1/A2 reactive astrocytes. The expression of CXCR7 and PI3K/Akt signaling was decreased after SMIR, while they were increased after treatment with minocycline. Furthermore, intrathecal injection of AMD3100 also relieved SMIR-induced mechanical allodynia, reverted the ratio of A1/A2 reactive astrocytes, and activated the PI3K/Akt signaling pathway, similar to the effects produced by minocycline. However, intrathecal injection of AMD3100 did not increase the analgesic effect of minocycline. Last, LY294002 inhibited the analgesic effect and A1/A2 transformation induced by minocycline and AMD3100 after SMIR. Conclusion: Our results indicated that microglia induce the transformation of astrocytes to the A1 phenotype in the spinal cord via downregulation of the CXCR7/PI3K/Akt signaling pathway during CPSP. Reverting A1 reactive astrocytes to A2 may represent a new strategy for preventing CPSP.

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Section: Discussionmentioning

confidence: 99%

Microglia induce the transformation of A1/A2 reactive astrocytes via the CXCR7/PI3K/Akt pathway in chronic post-surgical pain

Liu

Chen

et al. 2020

J Neuroinflammation

128

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“…Iba-1 is a marker of reactive microglia (Imai and Kohsaka 2002). Microglial activation presumably involves the FGF2/ FGFR1 (fibroblast growth factor and receptor) pathway as can be seen when this pathway is blocked (Zou et al 2019). Microglia play an important role in modulating inflammation, and especially the polarized (ARM) microglia contribute to a more regenerative environment.…”

Section: Iba-1mentioning

confidence: 99%

Why do anti-inflammatory signals of bone marrow-derived stromal cells improve neurodegenerative conditions where anti-inflammatory drugs fail?

et al. 2020

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Neurodegenerative disorders share the final degenerative pathway, the inflammation-induced apoptosis and/or necrosis, irrespective of their etiology, be it of acute and chronic traumatic, vascular and idiopathic origin. Although disease-modifying strategies are an unmet need in these disorders, lately, (pre)clinical studies suggested favorable effects after an intervention with bone marrow-derived stromal cells (bm-SC). Recent interventions with intrathecal transplantation of these cells in preclinical rodent models improved the functional outcome and reduced the inflammation, but not anti-inflammatory drugs. The benefit of bm-SCs was demonstrated in rats with an acute (traumatic spinal cord injury, tSCI) and in mice with a chronic [amyotrophic lateral sclerosis (ALS)-like FUS 1-358 or SOD1-G93-A mutation] neurodegenerative process. Bm-SCs, were found to modify underlying disease processes, to reduce final clinical SCI-related outcome, and to slow down ALS-like clinical progression. After double-blind interventions with bm-SC transplantations, Vehicle (placebo), and (non) steroidal anti-inflammatory drugs (Methylprednisolone, Riluzole, Celecoxib), clinical, histological and histochemical findings, serum/spinal cytokines, markers for spinal microglial activation inclusive, evidenced the cell-to-cell action of bm-SCs in both otherwise healthy and immune-deficient tSCI-rats, as well as wild-type and FUS/SOD1-transgenic ALS-like mice. The multi-pathway hypothesis of the cell-to-cell action of bmSCs, presumably using extracellular vesicles (EVs) as carriers of messages in the form of RNAs, DNA, proteins, and lipids rather than influencing a single inflammatory pathway, could be justified by the reported differences of cytokines and other chemokines in the serum and spinal tissue. The mode of action of bm-SCs is hypothesized to be associated with its dedicated adjustment of the pro-apoptotic glycogen synthase kinase-3β level towards an anti-apoptotic level whereas their multi-pathway hypothesis seems to be confirmed by the decreased levels of the pro-inflammatory interleukin (IL)-1β and tumor necrosis factor (TNF) as well as the level of the marker of activated microglia, ionized calcium binding adapter (Iba)-1 level.

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“…We demonstrate that NHP reactive astrocytes are not aligned with either the A1 or A2 astrocyte profiles previously identified in rodents 5,6 . Indeed, while a minor subset of A1 markers (MX1, SerpinG1, and FKBP5) were enriched in several reactive astrocyte subtypes, most A1 markers analysed were not, including crucial indicators such as PSMB8, SRGN and especially complement component C3, previously described as a surrogate marker of A1 astrocytes 5,[46][47][48] . Instead, all reactive astrocyte subtypes upregulated a combination of A1 and A2 markers.…”

Section: Discussionmentioning

confidence: 92%

Primate-specific response of astrocytes to stroke limits peripheral macrophage infiltration

Boghdadi

Spurrier

Teo

et al. 2020

Preprint

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Reactive astrocytes play critical roles after brain injuries but their precise function in stroke is not well defined. Here, we utilized single nuclei transcriptomics to characterize astrocytes after ischemic stroke in nonhuman primate (NHP) marmoset monkey primary visual cortex. We identified 19 putative subtypes of astrocytes from injured and uninjured brain hemispheres and observed nearly complete segregation between stroke and control astrocyte clusters. We then screened for genes that might be limiting stroke recovery and discovered that one neurite-outgrowth inhibitory protein, NogoA, previously associated with oligodendrocytes but not astrocytes, was expressed in numerous reactive astrocyte subtypes. NogoA upregulation on reactive astrocytes was confirmed in vivo for NHP and human, but not observed to the same extent in rodent. Further in vivo and in vitro studies determined that NogoA mediated an anti-inflammatory response which limits deeper infiltration of peripheral macrophages from the lesion during the subacute post-stroke period. Specifically, these findings are relevant to the development of NogoA-targeting therapies shortly after ischemic stroke. Our findings have uncovered the complexity and species specificity of astrocyte responses, which need to be considered more when investigating novel therapeutics for brain injury.

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Effects of FGF2/FGFR1 Pathway on Expression of A1 Astrocytes After Infrasound Exposure

Cited by 27 publications

References 20 publications

Microglia induce the transformation of A1/A2 reactive astrocytes via the CXCR7/PI3K/Akt pathway in chronic post-surgical pain

Microglia induce the transformation of A1/A2 reactive astrocytes via the CXCR7/PI3K/Akt pathway in chronic post-surgical pain

Why do anti-inflammatory signals of bone marrow-derived stromal cells improve neurodegenerative conditions where anti-inflammatory drugs fail?

Primate-specific response of astrocytes to stroke limits peripheral macrophage infiltration

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