Adenosine A2A Receptor Suppressed Astrocyte-Mediated Inflammation Through the Inhibition of STAT3/YKL-40 Axis in Mice With Chronic Cerebral Hypoperfusion-induced White Matter Lesions

Yuan, Jianmin; Chen, Lin; Wang, Jie; Xia, Simin; Huang, Jialu; Zhou, Linke; Feng, Chengjian; Hu, Xiaofei; Zhou, Zhenhua; Ran, Hong

doi:10.3389/fimmu.2022.841290

Cited by 7 publications

(7 citation statements)

References 35 publications

(38 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Thirdly, as an endothelial-related inflammatory mediator, YKL-40 could activate endothelial cells to induce intercellular adhesion molecule-1 expression, 37 which would further recruit leukocytes and release pro-inflammatory cytokines such as tumor necrosis factor-α, interleukin-1β and interferon-γ, leading to endothelial dysfunction and BBB disruption. 38 , 39 Additionally, according to the latest research, 30 YKL-40 expression in astrocytes was elevated in white matter lesions caused by chronic hypoxia, and downregulating the expression of YKL-40 significantly alleviate white matter injury, suggesting that YKL-40 is implicated in the process of white matter injury. Taken together, the mechanisms mentioned above might be significant contributors to YKL-40 with PV-WMH.…”

Section: Discussionmentioning

confidence: 98%

“…In a mouse model of WMH induced by chronic cerebral hypoperfusion, the expression of YKL-40 was shown to be elevated. 30 A recently published community-based study with 960 Chinese stroke-free participants observed a significant association between elevated levels of endothelial-related inflammatory biomarkers including YKL-40 and increased WMH volume. 9 In another study with 42 sporadic CSVD patients, CSF levels of YKL-40 were positively correlated with the WMH load.…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Serum YKL-40 Levels and White Matter Hyperintensities in Patients with Acute Ischemic Stroke

Shi¹,

Ke²,

Gong³

et al. 2023

JIR

View full text Add to dashboard Cite

Background White matter hyperintensity (WMH) is associated with risk of acute ischemic stroke (AIS) and poor outcomes after AIS. The purpose of this prospective study was to evaluate the association between serum YKL-40 levels and WMH burden in patients with AIS. Methods From February 2020 to March 2021, a total of 672 consecutive AIS patients with magnetic resonance imaging data were prospectively recruited form two centers. Serum YKL-40 levels were quantified using enzyme-linked immunosorbent assay. The burden of WMH was semiquantitatively measured by the Fazekas visual grading scale. According to severity of overall WMH, patients were dichotomized into none–mild WMH group (Fazekas score 0–2) or moderate–severe WMH group (Fazekas score 3–6). Besides, based on severity of periventricular WMH (PV-WMH) and deep WMH (D-WMH), patients were categorized as none–mild (Fazekas score 0–1) or moderate–severe (Fazekas score 2–3). Results Among the 672 patients, 335 (49.9%) participants were identified with moderate–severe overall WMH, 326 (48.5%) with moderate–severe PV-WMH and 262 (39.0%) with moderate–severe D-WMH. Compared with the first quartile of serum YKL-40, the adjusted odds ratio (OR) of the fourth quartile for moderate–severe PV-WMH was 2.473 (95% confidence interval [CI] 1.316–4.646; P =0.005). No significant association was observed between YKL-40 and overall WMH (OR 0.762; 95% CI 0.434–1.336; P =0.343) or D-WMH (OR 0.695; 95% CI 0.413–1.171; P =0.172). Conclusion Our results suggested that higher YKL-40 levels appeared to be associated with PV-WMH, but not with overall WMH or D-WMH in patients with AIS.

show abstract

Section: Discussionmentioning

confidence: 98%

Section: Discussionmentioning

confidence: 99%

Serum YKL-40 Levels and White Matter Hyperintensities in Patients with Acute Ischemic Stroke

Shi¹,

Ke²,

Gong³

et al. 2023

JIR

View full text Add to dashboard Cite

show abstract

“…Another study showed that the activation of adenosine A2A receptor could inhibit the expression of YKL-40 and thereby alleviate white matter injury in cerebral small vessel disease [24]. Furthermore, Bonneh-Barkay et al have reported that absence of YKL-40 in mice resulted in more pronounced neuroinflammation and gliosis, suggesting a potential role of YKL-40 as therapeutic candidate for modulating neuroinflammation [25].…”

Section: Discussionmentioning

confidence: 99%

Prognostic performance of serum YKL-40 for one-year clinical outcomes in acute ischemic stroke

Shi

et al. 2023

Aging

View full text Add to dashboard Cite

Background: Effects of YKL-40 on one-year clinical outcomes including poor clinical outcome, all-cause mortality, and stroke recurrence among acute ischemic stroke (AIS) patients remained elusive. The purpose of this study was to explore the association between serum YKL-40 at admission and one-year clinical outcomes in AIS patients. Methods: In this prospective cohort study, a total of 1002 participants out of 1361 AIS patients from two centers were included for current analysis. Serum YKL-40 concentrations were measured via enzyme-linked immunosorbent assay. Multivariable logistic or Cox regression were performed to explore the independent association of YKL-40 with one-year clinical outcomes, including poor outcome (modified Rankin Scale of 3-6), all-cause mortality, and recurrent stroke. C-statistic, net reclassification index (NRI) and integrated discrimination improvement (IDI) were calculated to evaluate the discriminatory and predictive power of YKL-40 when added to conventional model. Results: Compared with the first quartile of YKL-40, the adjusted odds ratios or hazard ratios with 95% confidence intervals of the fourth quartile were 3.032 (1.627-5.650) for poor outcome, 2.886 (1.320-6.308) for all-cause mortality and 1.694 (0.906-3.169) for recurrent stroke. The addition of serum YKL-40 to conventional model significantly improved reclassification for poor outcome (NRI 0.053, P = 0.031; IDI 0.018, P = 0.001) and all-cause mortality (NRI 0.162, P = 0.036). Conclusions: Elevated serum YKL-40 at admission might be independently associated with one-year poor outcome and all-cause mortality but not stroke recurrence among Chinese AIS patients.

show abstract

“…Its regulation has been shown to affect cognition in experimental models (Raber et al, 2014; Sun et al, 2020), and may activate Erk and Akt pathways and Wnt signalling (Geng et al, 2018), pathways associated with cognitive impairment (Albert-Gascó et al, 2020; Oliva et al, 2013; Shu et al, 2013). Of relevance, activation of the adenosine A2a receptor (ADORA2A), may decrease YKL-40 expression in astrocytes and alleviate neuroinflammation and white matter injury (Yuan et al, 2022). Dysregulation of ADORA2A in astrocytes has been shown to disrupt glutamate homeostasis leading to cognitive impairment, and in a SZ subgroup, reduced striatal ADORA2A levels is accompanied by an altered psychomotor phenotype (Matos et al, 2015).…”

Section: Discussionmentioning

confidence: 99%

Cognitive and inflammatory heterogeneity in severe mental illness: Translating findings from blood to brain

Sæther,

Szabo,

Akkouh

et al. 2023

Preprint

View full text Add to dashboard Cite

Recent findings link cognitive impairment and inflammatory-immune dysregulation in schizophrenia (SZ) and bipolar (BD) spectrum disorders. However, heterogeneity and translation between the periphery and central (blood-to-brain) mechanisms remains a challenge. Starting with a large SZ, BD and healthy control cohort (n=1235), we aimed to i) identify candidate peripheral markers (n=25) associated with cognitive domains (n=9) and elucidate heterogenous immune-cognitive patterns, ii) evaluate the regulation of candidate markers using human induced pluripotent stem cell (iPSC)-derived astrocytes and neural progenitor cells (n=10), and iii) evaluate candidate marker messenger RNA expression in leukocytes using microarray in available data from a subsample of the main cohort (n=776), and in available RNA-sequencing deconvolution analysis of postmortem brain samples (n=474) from the CommonMind Consortium (CMC). We identified transdiagnostic subgroups based on covariance between cognitive domains (measures of speed and verbal learning) and peripheral markers reflecting inflammatory response (CRP, sTNFR1, YKL-40), innate immune activation (MIF) and extracellular matrix remodelling (YKL-40, CatS). Of the candidate markers there was considerable variance in secretion of YKL-40 in iPSC-derived astrocytes and neural progenitor cells in SZ compared to HC. Further, we provide evidence of dysregulated RNA expression of genes encoding YKL-40 and related signalling pathways in a high inflammatory subgroup consisting predominantly of SZ in the postmortem brain samples. Our findings suggest a relationship between peripheral inflammatory-immune activity and cognitive impairment, and highlight YKL-40 as a potential marker of cognitive functioning in a subgroup of individuals with severe mental illness.

show abstract

Adenosine A2A Receptor Suppressed Astrocyte-Mediated Inflammation Through the Inhibition of STAT3/YKL-40 Axis in Mice With Chronic Cerebral Hypoperfusion-induced White Matter Lesions

Cited by 7 publications

References 35 publications

Serum YKL-40 Levels and White Matter Hyperintensities in Patients with Acute Ischemic Stroke

Serum YKL-40 Levels and White Matter Hyperintensities in Patients with Acute Ischemic Stroke

Prognostic performance of serum YKL-40 for one-year clinical outcomes in acute ischemic stroke

Cognitive and inflammatory heterogeneity in severe mental illness: Translating findings from blood to brain

Contact Info

Product

Resources

About