The regulatory role of ProBDNF in monocyte function: Implications in Stanford type‐A aortic dissection disease

Shen, Weiyun; Luo, Cong; Hurtado, Plinio R; Hurtado-Perez, E.; Luo, Ruyi; Hu, Zhao‐Lan; Li, Hui; Xu, Junmei; Zhou, Xin‐Fu; Dai, Renke

doi:10.1096/fj.201901905rr

Cited by 24 publications

(25 citation statements)

References 44 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Apoptosis may be triggered during early AAD stages, when intense inflammation causes severe tear of the aortic intima or when ischemia reperfusion of multi-organs stimulates release of pro-apoptotic substances, such as TNF-α and nitric oxide. Supporting this assumption, our recent study showed the serum derived from AAD patients activated gene expression of the pro-inflammatory cytokines in the cultured peripheral blood mononuclear cells from HDs ( 34 ).…”

Section: Discussionmentioning

confidence: 82%

Association of Apoptosis-Mediated CD4+ T Lymphopenia With Poor Outcome After Type A Aortic Dissection Surgery

Luo

Sun

Tang

et al. 2021

Front. Cardiovasc. Med.

Self Cite

View full text Add to dashboard Cite

Background: Many patients with type A aortic dissection (AAD) show low lymphocyte counts pre-operatively. The present study investigated the prognostic values of lymphopenia and lymphocyte subsets for the postoperative major adverse events (MAEs) in AAD patients undergoing surgery, and explore mechanisms of lymphopenia.Methods: We retrospectively analyzed pre-operative lymphocyte counts in 295 AAD patients treated at two hospitals, and evaluated their correlation with MAEs. We prospectively recruited 40 AAD patients and 20 sex- and age-matched healthy donors (HDs), and evaluated lymphocyte subsets, apoptosis, and pyroptosis by flow cytometry.Results: Multivariable regression analysis of the retrospective cohort revealed pre-operative lymphopenia as a strong predictor of MAEs (odds ratio, 4.152; 95% CI, 2.434–7.081; p < 0.001). In the prospective cohort, lymphocyte depletion in the AAD group was mainly due to loss of CD4+ and CD8+ T cells as compared with HDs (CD4+ T cells: 346.7 ± 183.6 vs. 659.0 ± 214.6 cells/μl, p < 0.0001; CD8+ T cells: 219.5 ± 178.4 vs. 354.4 ± 121.8 cells/μl, p = 0.0036). The apoptosis rates of CD4+ and CD8+ T cells were significantly higher in AAD patients relative to HDs (both p < 0.0001). Furthermore, the pre-operative CD4+ T cells count at a cut-off value of 357.96 cells/μl was an effective and reliable predictor of MAEs (area under ROC curve = 0.817; 95% CI, 0.684-0.950; sensitivity, 74%; specificity, 81%; p < 0.005). Pre-operative lymphopenia, mainly due to CD4+ T cells exhaustion by apoptosis, correlates with poor prognosis in AAD patients undergoing surgery.Conclusion: Pre-operative lymphopenia in particular CD4+ T lymphopenia via apoptosis correlates with poor prognosis in AAD patients undergoing surgery.

show abstract

Section: Discussionmentioning

confidence: 82%

Association of Apoptosis-Mediated CD4+ T Lymphopenia With Poor Outcome After Type A Aortic Dissection Surgery

Luo

Sun

Tang

et al. 2021

Front. Cardiovasc. Med.

Self Cite

View full text Add to dashboard Cite

show abstract

“…ProBDNF staining was conducted as our previous study [21]. Washed cells that had been stained with above extracellular markers were fixed by fixation buffer (Invitrogen, USA, catalog: 2060489) for 20 min at room temperature and followed by permeabilization as introduced by the manufacturer protocol (Invitrogen, USA, catalog: 2009161).…”

Section: Flow Cytometrymentioning

confidence: 99%

“…Splenocytes were resuspended in DMEM supplemented with 10% heat-inactivated FBS, 2 mM glutamine, 25 mM HEPES (all from Gibco, USA), 5 × 10 −5 M 2-ME (Solarbio, China), and 100 U ml −1 penicillin. 4 × 10 5 cells were put in each well of a 96-well flat-bottom plate and stimulated with 100, 200, or 500 ng ml −1 proBDNF protein (Alomone Labs, Israel, catalog: B243) as introduced by our previous studies [21], respectively. 72 h later, splenocytes were collected and analyzed by flow cytometry as indicated above.…”

Section: Cell Culturementioning

confidence: 99%

ProBDNF promotes sepsis-associated encephalopathy in mice by dampening the immune activity of meningeal CD4+ T cells

Luo

Zhong

et al. 2020

J Neuroinflammation

Self Cite

View full text Add to dashboard Cite

Background: Sepsis-associated encephalopathy (SAE) increases the mortality of septic patients, but its mechanism remains unclear. The present study aimed to investigate the roles of T lymphocytes, proBDNF, and their interaction in the pathogenesis of SAE. Methods: Fear conditioning tests were conducted for cognitive assessment in the lipopolysaccharide (LPS, 5 mg kg −1)-induced septic mice. Meninges and peripheral blood were harvested for flow cytometry or qPCR. FTY720 and monoclonal anti-proBDNF antibody (McAb-proB) were used to investigate the effect of lymphocyte depletion and blocking proBDNF on the impaired cognitive functions in the septic mice. Results: In the septic mice, cognitive function was impaired, the percentage of CD4 + T cells were decreased in the meninges (P = 0.0021) and circulation (P = 0.0222), and pro-inflammatory cytokines were upregulated, but the antiinflammatory cytokines interleukin (IL)-4 (P < 0.0001) and IL-13 (P = 0.0350) were downregulated in the meninges. Lymphocyte depletion by intragastrically treated FTY720 (1 mg kg −1) for 1 week ameliorated LPS-induced learning deficit. In addition, proBDNF was increased in the meningeal (P = 0.0042) and peripheral (P = 0.0090) CD4 + T cells. Intraperitoneal injection of McAb-proB (100 μg) before LPS treatment significantly alleviated cognitive dysfunction, inhibited the downregulation of meningeal (P = 0.0264) and peripheral (P = 0.0080) CD4 + T cells, and normalized the gene expression of cytokines in the meninges. However, intra-cerebroventricular McAb-proB injection (1 μg) did not have such effect. Finally, exogenous proBDNF downregulated the percentage of CD4 + T cells in cultured splenocytes from septic mice (P = 0.0021). Conclusion: Upregulated proBDNF in immune system promoted the pathogenesis of SAE through downregulating the circulating CD4 + T cells, limiting its infiltration into the meninges and perturbing the meningeal pro-/antiinflammatory homeostasis.

show abstract

“…We have revealed a pro-in ammatory effect of in ltrating MDMs restricted probably to between day 3 and 7 post-injury, while later resident microglia increased their conversion to an M2 phenotype that enhanced endogenous repair. Importantly, in a previous study [41] we reported an increased ratio of M1/M2-like monocytes in the peripheral circulation in patients with Stanford type-A aortic dissection (AAD), indicating that once AAD patients are subjected to the process of deep hypothermic circulatory arrest, increased numbers of M1 polarized macrophages migrate to the re-perfused spinal cord, aggravating the severity of in ammation in the micro-environment of the site of the lesion. Thus, a better understanding of the differential phenotypes of activated resident microglia and in ltrating MDMs following CNS might enable the development of novel approaches to attenuate SCIRI, for example, by timely targeting in ltrating monocytes through regulation of monocyte migration and intracellular signaling may help for the recovery.…”

Section: Discussionmentioning

confidence: 96%

Distinct Polarization Dynamics of Microglia and Infiltrating Macrophages: A Novel Mechanism of Spinal Cord Ischemia/reperfusion Injury

Yang

Tang

Sun

et al. 2021

Preprint

Self Cite

View full text Add to dashboard Cite

Background: Macrophages arising from microglia and monocyte-derived macrophages (MDMs) have extensively studied and characterized in spinal corda injury. However, the infiltration of MDMs and the precise phenotypes of the two different populations during spinal cord ischemia and reperfusion injury (SCIRI), remains ambiguous. Methods: The SCIRI model was established by transient aortic occlusion followed by reperfusion. The Basso mouse scale (BMS) was used to quantify hind limb locomotion over the following three weeks. The histopathology of the spinal cord was evaluated by hematoxylin-eosin (HE) staining and NF-200 histochemistry. In addition, the expression of macrophage polarization phenotype were observed by double immunofluorescences, real-time PCR, and flow cytometry. Results: Compared with the Sham group, all mice in the SCIRI group developed acute paraplegia after reperfusion, gradually recovering neurological function by day 21. HE staining revealed that SCIRI induced evident pathological changes in the spinal cord. M1-type genes (iNOS, TNF-α, CD86, and CD16) were dramatically upregulated, mainly during the 1st week of SCIRI, whereas the M2 genes, CD206, and CD204, were elevated at a later stage. In addition, double-immunofluorescence confirmed in these activated microglia/macrophages phenotypes that CD86 and CD206 were co-localized. Finally, flow cytometry further demonstrated the infiltration of MDMs (CD11b+ CD45high cells) that were principally a pro-inflammatory M1 type, which peaked at day 3 and decreased by day 7 post-injury. Conversely, microglia (CD11b+CD45low cells), rather than invading MDMs, was the principal source of M2 polarized cells.Conclusions: SCIRI induced a transient influx of MDMs characterized by a M1 pro-inflammatory type, whereas resident microglia essentially maintained an M2 anti-inflammatory phenotype at later stage. These findings suggest that there is a differential regulatory role in the two cell populations following SCIRI.

show abstract

The regulatory role of ProBDNF in monocyte function: Implications in Stanford type‐A aortic dissection disease

Cited by 24 publications

References 44 publications

Association of Apoptosis-Mediated CD4+ T Lymphopenia With Poor Outcome After Type A Aortic Dissection Surgery

Association of Apoptosis-Mediated CD4+ T Lymphopenia With Poor Outcome After Type A Aortic Dissection Surgery

ProBDNF promotes sepsis-associated encephalopathy in mice by dampening the immune activity of meningeal CD4+ T cells

Distinct Polarization Dynamics of Microglia and Infiltrating Macrophages: A Novel Mechanism of Spinal Cord Ischemia/reperfusion Injury

Contact Info

Product

Resources

About