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Mesenchymal stem cells suppress neuronal apoptosis and decrease IL-10 release via the TLR2/NFκB pathway in rats with
Yan Gu1,2,3, Yun Zhang4,5,6, Yang Bi7,8
1Children Nutrition Research Centre, Children's Hospital of Chongqing Medical University, Chongqing, 400014, China. lydoctorgy@163.com.
Insights
Mesenchymal stem cell transplantation improves hypoxic-ischemic brain damage (HIBD) by suppressing Toll-like receptor 2 (TLR2) and nuclear factor kappa B (NFκB) signaling. This pathway inhibition reduces inflammation and enhances learning-memory function in affected infants.
Area of Science:
- Neuroscience
- Immunology
- Regenerative Medicine
Background:
- Hypoxic-ischemic brain damage (HIBD) is a significant cause of infant mortality and long-term neurological deficits.
- Mesenchymal stem cell (MSC) transplantation shows promise in mitigating HIBD through immunomodulatory effects.
- The specific mechanisms involving Toll-like receptor 2 (TLR2) and interleukin-10 (IL-10) in MSC-mediated HIBD recovery require elucidation.
Purpose of the Study:
- To investigate the role of TLR2 and IL-10 in the immunomodulatory effects of MSCs on HIBD.
- To elucidate the signaling pathways targeted by MSCs to restore function after HIBD.
Main Methods:
- Utilized a rat model of HIBD and in vitro oxygen-glucose deprivation (OGD) models with PC12 cells.
- Administered MSC transplantation and employed TLR2 agonists (Pam3CSK4) and small interfering RNA (siTLR2) for mechanistic studies.
- Assessed learning-memory function, apoptosis markers (Bax), and key signaling molecules (TLR2, IL-10, NFκB) via molecular assays.
Main Results:
- MSC transplantation in HIBD rats downregulated TLR2 expression and IL-10 release, improving learning-memory deficits.
- Activation of TLR2 with Pam3CSK4 exacerbated HIBD, increasing NFκB, Bax, and IL-10 levels.
- In vitro, MSC co-culture inhibited the TLR2/NFκB pathway, reducing Bax and IL-10 in OGD-injured cells.
Conclusions:
- TLR2 plays a critical role in HIBD pathogenesis.
- MSCs ameliorate HIBD by suppressing the TLR2/NFκB signaling pathway, leading to reduced apoptosis and improved cognitive function.
- Targeting the TLR2/NFκB pathway represents a potential therapeutic strategy for HIBD treatment.
Background:
Hypoxic-ischemic brain damage (HIBD) is a major cause of infant mortality and neurological disability in children. Many studies have demonstrated that mesenchymal stem cell (MSC) transplantation facilitates the restoration of the biological function of injured tissue following HIBD via immunomodulation. This study aimed to elucidate the mechanisms by which MSCs mediate immunomodulation via the key effectors Toll-like receptor 2 (TLR2) and interleukin-10 (IL-10).
Results:
We showed that TLR2 expression in the brain of HIBD rats was upregulated following HIBD and that MSC transplantation suppressed the expression of TLR2 and the release of IL-10, thereby alleviating the learning-memory deficits of HIBD rats. Following treatment with the specific TLR2 agonist Pam3CSK4 to activate TLR2, learning-memory function became further impaired, and the levels of nuclear factor kappa B (NFκB) and Bax expression and IL-10 release were significantly increased compared with those in HIBD rats that did not receive Pam3CSK4. In vitro, we found that MSC co-culture downregulated TLR2/NFκB signaling and repressed Bax expression and IL-10 secretion in oxygen and glucose deprivation (OGD)-injured adrenal pheochromocytoma (PC12) cells. Furthermore, NFκB and Bax expression and IL-10 release were enhanced following Pam3CSK4 treatment and were decreased following siTLR2 treatment in OGD-injured PC12 cells in the presence or absence of MSCs.
Conclusions:
Our data indicate that TLR2 is involved in HIBD and that MSCs decrease apoptosis and improve learning-memory function in HIBD rats by suppressing the TLR2/NFκB signaling pathway via a feedback mechanism that reduces IL-10 release. These findings strongly suggest that MSC transplantation improves HIBD via the inhibition of the TLR2/NFκB pathway.
