Critical role of Tim-3 mediated autophagy in chronic stress induced immunosuppression

Qin, Anna; Zhong, Ting; Zou, Huajiao; Wan, Xiaoya; Yao, Bifeng; Zheng, Xinbin; Yin, Deling

doi:10.1186/s13578-019-0275-1

Cited by 14 publications

(10 citation statements)

References 43 publications

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“…Inflammation mediators can disrupt the clearance of misfolded proteins. To the contrary, the impaired autophagy causes inflammation [46]. We found that the lysosomal functional protein, represented by the expression of RAB7 and LAMP1 were decreased in the stressed microglia, while RAGE −/− in microglia reversed this effect and increased the acidity of lysosome.…”

Section: Discussionmentioning

confidence: 77%

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HMGB1/RAGE axis mediates stress-induced RVLM neuroinflammation in mice via impairing mitophagy flux in microglia

Zhang

Jiang

et al. 2020

J Neuroinflammation

115

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Background: Microglial mediated neuroinflammation in the rostral ventrolateral medulla (RVLM) plays roles in the etiology of stress-induced hypertension (SIH). It was reported that autophagy influenced inflammation via immunophenotypic switching of microglia. High-mobility group box 1 (HMGB1) acts as a regulator of autophagy and initiates the production of proinflammatory cytokines (PICs), but the underlying mechanisms remain unclear. Methods: The stressed mice were subjected to intermittent electric foot shocks plus noises administered for 2 h twice daily for 15 consecutive days. In mice, blood pressure (BP) and renal sympathetic nerve activity (RSNA) were monitored by noninvasive tail-cuff method and platinum-iridium electrodes placed respectively. Microinjection of siRNA-HMGB1 (siHMGB1) into the RVLM of mice to study the effect of HMGB1 on microglia M1 activation was done. mRFP-GFP-tandem fluorescent LC3 (tf-LC3) vectors were transfected into the RVLM to evaluate the process of autolysosome formation/autophagy flux. The expression of RAB7, lysosomal-associated membrane protein 1 (LAMP1), and lysosomal pH change were used to evaluate lysosomal function in microglia. Mitophagy was identified by transmission electron microscopic observation or by checking LC3 and MitoTracker colocalization under a confocal microscope. Results: We showed chronic stress increased cytoplasmic translocations of HMGB1 and upregulation of its receptor RAGE expression in microglia. The mitochondria injury, oxidative stress, and M1 polarization were attenuated in the RVLM of stressed Cre-CX3CR1/RAGE fl/fl mice. The HMGB1/RAGE axis increased at the early stage of stress-induced mitophagy flux while impairing the late stages of mitophagy flux in microglia, as revealed by decreased GFP fluorescence quenching of GFP-RFP-LC3-II puncta and decreased colocalization of lysosomes with mitochondria. The expressions of RAB7 and LAMP1 were decreased in the stressed microglia, while knockout of RAGE reversed these effects and caused an increase in acidity of lysosomes. siHMGB1 in the RVLM resulted in BP lowering and RSNA decreasing in SIH mice. When the autophagy inducer, rapamycin, is used to facilitate the mitophagy flux, this treatment results in attenuated NF-κB activation and reduced PIC release in exogenous disulfide HMGB1 (ds-HMGB1)-stimulated microglia. Conclusions: Collectively, we demonstrated that inhibition of the HMGB1/RAGE axis activation led to increased stress-induced mitophagy flux, hence reducing the activity of microglia-mediated neuroinflammation and consequently reduced the sympathetic vasoconstriction drive in the RVLM.

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Section: Discussionmentioning

confidence: 77%

“…Evidences show psychological and physical stress can either enhance or suppress immune responses depending on a variety of factors such as duration and severity of stressful situation. Mitophagy flux involves the activation, inflammatory response, and survival of microglia [46,47]; however, the detailed mechanisms remain largely unknown.…”

Section: Discussionmentioning

confidence: 99%

HMGB1/RAGE axis mediates stress-induced RVLM neuroinflammation in mice via impairing mitophagy flux in microglia

Zhang

Jiang

et al. 2020

J Neuroinflammation

115

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“…Cytokines play an important role in Plasmodium infection [28] and the levels of cytokines are associated with the expression of Tim-3 [29]. Thus, the presence of IL-2, IL-4, IL-6, IL-9, IL-10, IL-22, TNF-α, and IFN-γ in the mouse sera at days 4, 9, 11, 13 and 14 p.i.…”

Section: Resultsmentioning

confidence: 99%

Tim-3 signaling blockade with α-lactose induces compensatory TIGIT expression in Plasmodium berghei ANKA-infected mice

et al. 2019

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BackgroundMalaria, one of the largest health burdens worldwide, is caused by Plasmodium spp. infection. Upon infection, the host’s immune system begins to clear the parasites. However, Plasmodium species have evolved to escape the host’s immune clearance. T-cell immunoglobulin and mucin domain 3 (Tim-3), a surface molecule on most immune cells, is often referred to as an exhaustion marker. Galectin (Gal)-9 is a Tim-3 ligand and the T helper (Th) 1 cell response is inhibited when Gal-9 binds to Tim-3. In the present study, dynamic expression of Tim-3 on key populations of lymphocytes during infection periods of Plasmodium berghei and its significance in disease resistance and pathogenesis were explored.MethodsTim-3 expression on critical lymphocyte populations and the proportion of these cells, as well as the levels of cytokines in the sera of infected mice, were detected by flow cytometry. Further, in vitro anti-Tim-3 assay using an anti-Tim-3 antibody and in vivo Tim-3-Gal-9 signaling blockade assays using α-lactose (an antagonist of Gal-9) were conducted. An Annexin V Apoptosis Detection Kit with propidium iodide was used to detect apoptosis. In addition, proteins associated with apoptosis in lung and spleen tissues were confirmed by Western blotting assays.ResultsIncreased Tim-3 expression on splenic CD8+ and splenic CD4+, and circulatory CD4+ T cells was associated with a reduction in the proportion of these cells. Furthermore, the levels of interleukin (IL)-2, IL-4, IL-6, IL-22, and interferon (IFN)-γ, but not that of tumor necrosis factor alpha (TNF-α), IL-10, and IL-9, increased to their highest levels at day 4 post-infection and decreased thereafter. Blocking Tim-3 signaling in vitro inhibited lymphocyte apoptosis. Tim-3-Gal-9 signaling blockade in vivo did not protect the mice, but induced the expression of the immunosuppressive molecule, T cell immunoreceptor with Ig and ITIM domains (TIGIT), in Plasmodium berghei ANKA-infected mice.ConclusionsTim-3 on lymphocytes negatively regulates cell-mediated immunity against Plasmodium infection, and blocking Tim-3-galectin 9 signaling using α-lactose did not significantly protect the mice; however, it induced the compensatory expression of TIGIT. Further investigations are required to identify whether combined blockade of Tim-3 and TIGIT signaling could achieve a better protective effect.

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“…Similar results have been observed in vivo by using a placenta-specific Atg7 (essential for autophagy) conditional knockout mouse model [ 68 ], which results in autophagy deficiency accompanied by poor placentation and elevated maternal blood pressure, suggesting its correlation with the pathophysiology of PE. Notably, both Gal-3 and Gal-9 have been implicated in the control of autophagy, acting as negative (Gal-3 [ 69 ]) and positive (Gal-9, mediated by polyLacNAc recognition [ 70 , 71 ]) modulators, respectively. These findings are in agreement with our observation that SHRSP implantations exhibited decreased Gal-9 and upregulated Gal-3 levels already at the onset of the disease and reduced polyLacNAc presentation (LEA staining) in placental compartments, which would possibly lead to impaired autophagy und thus cellular stress.…”

Section: Discussionmentioning

confidence: 99%

Placental Glycoredox Dysregulation Associated with Disease Progression in an Animal Model of Superimposed Preeclampsia

Blois

Prince

Borowski

et al. 2021

Cells

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Pregnancies carried by women with chronic hypertension are at increased risk of superimposed preeclampsia, but the placental pathways involved in disease progression remain poorly understood. In this study, we used the stroke-prone spontaneously hypertensive rat (SHRSP) model to investigate the placental mechanisms promoting superimposed preeclampsia, with focus on cellular stress and its influence on galectin–glycan circuits. Our analysis revealed that SHRSP placentas are characterized by a sustained activation of the cellular stress response, displaying significantly increased levels of markers of lipid peroxidation (i.e., thiobarbituric acid reactive substances (TBARS)) and protein nitration and defective antioxidant enzyme expression as early as gestation day 14 (which marks disease onset). Further, lectin profiling showed that such redox imbalance was associated with marked alterations of the placental glycocode, including a prominent decrease of core 1 O-glycan expression in trophoblasts and increased decidual levels of sialylation in SHRSP placentas. We also observed significant changes in the expression of galectins 1, 3 and 9 with pregnancy progression, highlighting the important role of the galectin signature as dynamic interpreters of placental microenvironmental challenges. Collectively, our findings uncover a new role for the glycoredox balance in the pathogenesis of superimposed preeclampsia representing a promising target for interventions in hypertensive disorders of pregnancy.

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Critical role of Tim-3 mediated autophagy in chronic stress induced immunosuppression

Cited by 14 publications

References 43 publications

HMGB1/RAGE axis mediates stress-induced RVLM neuroinflammation in mice via impairing mitophagy flux in microglia

HMGB1/RAGE axis mediates stress-induced RVLM neuroinflammation in mice via impairing mitophagy flux in microglia

Tim-3 signaling blockade with α-lactose induces compensatory TIGIT expression in Plasmodium berghei ANKA-infected mice

Placental Glycoredox Dysregulation Associated with Disease Progression in an Animal Model of Superimposed Preeclampsia

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