Injury-stimulated Sonic hedgehog expression in microglia contributes to neuroinflammatory response in the MPTP model of Parkinson's disease

Lee, Jeong Hwi; Chung, Young Cheul; Bok, Eugene; Lee, Hankyu; Huh, Sue H.; Lee, Ji Eun; Jin, Byung Kwan; Ko, Hyuk Wan

doi:10.1016/j.bbrc.2016.11.144

Cited by 13 publications

(11 citation statements)

References 27 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The disorder of the Shh signal transduction in the brain would lead to the occurrence of various nervous system diseases, such as brain tumours, 70 Parkinson's disease, 71 epilepsy, 72 autism, 73 depression 74 and traumatic brain injury 75 (overall symptoms of the Shh‐related CNS diseases are summarized in Table 1).…”

Section: Effect Of Shh Signal Pathway On Cnsmentioning

confidence: 99%

The role of Shh signalling pathway in central nervous system development and related diseases

et al. 2020

Cell Biochemistry & Function

View full text Add to dashboard Cite

Sonic hedgehog (Shh) plays important roles in developmental of vertebrate animal central nervous system (CNS), and Gli is its downstream signal molecule. Shh signalling is essential for pattern formation, cell‐fate specification, axon guidance, proliferation, survival and differentiation of neurons in CNS development. The abnormal signalling pathway of Shh leads to the occurrence of many nervous system diseases. The mechanism of Shh signalling is complex and remains incompletely understood. Nevertheless, studies have revealed that Shh signalling pathway is classified into canonical and non‐canonical pathways. Here we review the role of the Shh signalling pathway and its impact in CNS development and related diseases. Specifically, we discuss the role of Shh in the spinal cord and brain development, cell differentiation and proliferation in CNS and related diseases such as brain tumour, Parkinson's diseases, epilepsy, autism, depression and traumatic brain injury. We also highlight future directions of research that could help to clarify the mechanisms and consequences of Shh signalling in the process of CNS development and related diseases. Significance of the study This review summarized the role of Shh signalling pathway in CNS development and related diseases such as brain tumour, Parkinson's diseases, epilepsy, autism, depression and traumatic brain injury. It also presented the author's opinions on the future research direction of Shh signalling pathway.

show abstract

Section: Effect Of Shh Signal Pathway On Cnsmentioning

confidence: 99%

The role of Shh signalling pathway in central nervous system development and related diseases

et al. 2020

Cell Biochemistry & Function

View full text Add to dashboard Cite

show abstract

“…Involvement of SHH in synaptic plasticity was also reported (20). SHH expression is activated upon traumatic injury in the brain (21,22) including in astrocytes (21,23). During injury, released SHH increases the expression of glial fibrillary acidic protein in astrocytes and induces transformation of astrocytes to reactive astrocytes.…”

Section: Shh In the Cnsmentioning

confidence: 80%

“…Although the intercellular and intracellular signaling mechanisms that make astrocytes reactive and form scars are not well-characterized, an increase in extracellular ATP has been implicated in the initial microglial activation (78), leading to transformation of astrocytes to the reactive state (79). Although it is proposed that ATP is released from injured cells as "find me" (80) or "eat me" (81) signals, intact astrocytes could be involved in the increase in extracellular ATP in the early phase of the response to injury by responding to SHH release because SHH levels are raised after traumatic brain injury (21,22). SHH is also expressed after brain ischemia (82), and administration of SHH to rats just after stroke partially relieves neurological damage with improved angiogenesis and neuron survival (83).…”

Section: Shh Enhances Ca Oscillations In Astrocytesmentioning

confidence: 99%

Sonic hedgehog enhances calcium oscillations in hippocampal astrocytes

Adachi

Kakinuma

et al. 2019

Journal of Biological Chemistry

View full text Add to dashboard Cite

Edited by Roger J. Colbran Sonic hedgehog (SHH) is important for organogenesis during development. Recent studies have indicated that SHH is also involved in the proliferation and transformation of astrocytes to the reactive phenotype. However, the mechanisms underlying these are unknown. Involvement of SHH signaling in calcium (Ca) signaling has not been extensively studied. Here, we report that SHH and Smoothened agonist (SAG), an activator of the signaling receptor Smoothened (SMO) in the SHH pathway, activate Ca oscillations in cultured murine hippocampal astrocytes. The response was rapid, on a minute time scale, indicating a noncanonical pathway activity. Pertussis toxin blocked the SAG effect, indicating an involvement of a G i coupled to SMO. Depletion of extracellular ATP by apyrase, an ATP-degrading enzyme, inhibited the SAG-mediated activation of Ca oscillations. These results indicate that SAG increases extracellular ATP levels by activating ATP release from astrocytes, resulting in Ca oscillation activation. We hypothesize that SHH activates SMO-coupled Gi in astrocytes, causing ATP release and activation of G q/11 -coupled P2 receptors on the same cell or surrounding astrocytes. Transcription factor activities are often modulated by Ca patterns; therefore, SHH signaling may trigger changes in astrocytes by activating Ca oscillations. This enhancement of Ca oscillations by SHH signaling may occur in astrocytes in the brain in vivo because we also observed it in hippocampal brain slices. In summary, SHH and SAG enhance Ca oscillations in hippocampal astrocytes, G i mediates SAG-induced Ca oscillations downstream of SMO, and ATP-permeable channels may promote the ATP release that activates Ca oscillations in astrocytes.

show abstract

“…Local inhibition of the Hh pathway facilitated endoneurial and perineurial vascular permeability following trigeminal nerve injury, thereby facilitating immunocyte infiltration and neuroinflammation [19]. Shh expression was gradually increased in the MPTP (1-methyl-4-phenyl-1, 2,3, 6-tetrahydropyridine) model of Parkinson's disease, and was involved in the recovery from neurotoxin-induced injury [20]. It was found that Shh protected dopaminergic neurons and attenuated the inflammatory response by stimulating the PI3K/Akt pathway and increasing the expression of transforming growth factor-β (TGF-β) [21].…”

Section: Discussionmentioning

confidence: 99%

Gli2 Mediated Activation of Hedgehog Signaling Attenuates Acute Pancreatitis via Balancing Inflammatory Cytokines in Mice

Liu

Lai

Xie

et al. 2018

Cell Physiol Biochem

View full text Add to dashboard Cite

Background/Aims: Inflammatory response is a determinant in the pathological progression of acute pancreatitis (AP). Previous studies have shown that the activation of hedgehog (Hh) signaling is a remarkable change in caerulein-induced AP. However, the relationship between Hh signaling and inflammation is largely ambiguous. Methods: The AP mouse model was induced by injection of cerulein, and histological staining and serum enzymology assays were used to evaluate the establishment of AP. Western blot assay was used to determine the protein levels, cleavage of apoptotic proteins, and activation of the NF-κB signaling pathway. Cytokine array was used to screen inflammatory cytokines, and target cytokines’ transcriptional expression and serum levels were examined by real-time PCR and enzyme-linked immunosorbent assay, respectively. Results: The key transcriptional factor in Hh signaling, Gli2, was upregulated in the pancreas and other tissues during the process of AP, and it seems to be a characteristic feature of local inflammation in pancreatic tissue and systemic inflammatory response in multiple organs. The inflammatory NF-κB pathway is required for the activation of Hh signaling, as blockade of the NF-κB pathway by pyrrolidine dithiocarbamate impaired the Gli2 upregulation. Manipulation of Gli2 expression altered the activation of the NF-κB pathway correspondingly, as well as the cell apoptosis in cerulein-induced AP. Moreover, Gli2 upregulation changed the cytokine expression profile in mouse pancreatic acinar cells, mainly decreasing the pro-inflammatory cytokines interleukin (IL)-6, interferon-γ, and FasL. The anti-inflammatory cytokine IL-10 was upregulated by Gli2 overexpression. Interdiction of Gli2 by the Gli-specific inhibitor GANT61 exacerbated AP in mice and altered the balance of inflammatory cytokines. Conclusions: This study indicates that Hh activation during AP development is a negative feedback of the inflammatory response, restricting inflammatory injury to the pancreas and other tissues. Thus, manipulation of Hh signaling should shed light on limiting inflammation and alleviating AP damage.

show abstract

Injury-stimulated Sonic hedgehog expression in microglia contributes to neuroinflammatory response in the MPTP model of Parkinson's disease

Cited by 13 publications

References 27 publications

The role of Shh signalling pathway in central nervous system development and related diseases

The role of Shh signalling pathway in central nervous system development and related diseases

Sonic hedgehog enhances calcium oscillations in hippocampal astrocytes

Gli2 Mediated Activation of Hedgehog Signaling Attenuates Acute Pancreatitis via Balancing Inflammatory Cytokines in Mice

Contact Info

Product

Resources

About