Rapamycin Modulates the Proinflammatory Memory-Like Response of Microglia Induced by BAFF

Wang, Jianbo; Yang, Chunshu; Hou, Xiaoyu; Xu, Jingyi; Yang, Yun; Qin, Ling; Yang, Pingting

doi:10.3389/fimmu.2021.639049

Cited by 11 publications

(13 citation statements)

References 45 publications

(83 reference statements)

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“…5A). BAFF belongs to the TNF family and plays a vital role in the survival of B-lymphocytes (15). We confirmed that PMN-MDSCs from CIA mice expressed higher levels of BAFF than those from DBA/1J mice (Fig.…”

Section: Pmn-mdscs Modulated B Cells Via Baffsupporting

confidence: 76%

Polymorphonuclear myeloid-derived suppressor cells play a proinflammatory role via TNF-α + B cells through BAFF/BTK/NF-B signaling pathway in the pathogenesis of collagen-induced arthritis mice

Tang²,

Wu³

et al. 2023

Preprint

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Objectives: Although various studies have been performed on the function of polymorphonuclear myeloid-derived suppressor cells (PMN-MDSCs) in RA, the results were conflicting. Here we were trying to clarify the role of PMN-MDSCs in the pathogenesis of RA and its specific mechanisms. Methods: We detected the frequencies and counts of PMN-MDSCs, TNF- B cells, and Ki67 B cells in spleens and inflamed joints of collagen-induced arthritis (CIA) mice using flow cytometry. The pathological role of PMN-MDSCs was examined by anti-Ly6G neutralizing antibodies against PMN-MDSCs or adoptive transfer of PMN-MDSCs. And the modulation of PMN-MDSCs on B cells was conducted by coculture assays, RNA-Seq, RT-qPCR, etc. The mechanism of BAFF regulating B cells was verified through Western Blot and flow cytometry. Results: PMN-MDSCs accumulated in the spleens and joints of CIA mice. PMN-MDSCs depletion could alleviate the arthritis severity, which was accompanied by decreased TNF- secretion and proliferation of B cells. And its adoptive transfer also facilitated disease progress. Furthermore, PMN-MDSCs from CIA mice had higher expression level of BAFF, which regulated TNF- expression, proliferation and apoptosis of B cells in vitro. What’s more, BAFF promoted phosphorylation of BTK/NF-B signaling pathway. And Ibrutinib (BTK inhibitor) could reverse the effect of BAFF on TNF- expression. Conclusions: Our study suggested that PMN-MDSCs enhanced disease severity of CIA and manipulated TNF- expression, proliferation and apoptosis of B cells via BAFF, furthermore, BAFF promoted TNF- expression through BTK/NF-B signaling pathway, which demonstrated a novel pathogenesis of PMN-MDSC in CIA.

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Section: Pmn-mdscs Modulated B Cells Via Baffsupporting

confidence: 76%

Polymorphonuclear myeloid-derived suppressor cells play a proinflammatory role via TNF-α + B cells through BAFF/BTK/NF-B signaling pathway in the pathogenesis of collagen-induced arthritis mice

Tang²,

Wu³

et al. 2023

Preprint

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“… 115 Similar to experimental models of trained immunity, 4 weeks after infection of mice with Salmonella typhimurium , microglia had greater immune reactivity and exaggerated local inflammatory responses to subsequent stimulation with LPS. 116 Recently, rapamycin was shown to suppress the trained immunity‐like responses of microglia through targeting the mTOR/HIF‐1α signaling pathway, 117 providing novel insights into current therapeutic strategies in neurodegenerative diseases.…”

Section: The Yin‐yang Balance Of Trained Immunitymentioning

confidence: 99%

Trained immunity: A Yin‐Yang balance

Lowrie

et al. 2022

MedComm

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Traditionally, immune memory is regarded as an exclusive hallmark of adaptive immunity. However, a growing body of evidence suggesting that innate immune cells show adaptive characteristics has challenged this dogma. In the past decade, trained immunity, a de facto innate immune memory, has been defined as a long‐term functional reprogramming of cells of the innate immune system: the reprogramming is evoked by endogenous or exogenous insults, the cells return to a nonactivated state and subsequently show altered inflammatory responses against a second challenge. Trained immunity became regarded as a mechanism selected in evolution to protect against infection; however, a maladaptive effect might result in hyperinflammation. This dual effect is consistent with the Yin‐Yang theory in traditional Chinese philosophy, in which Yang represents active, positive, and aggressive factors, whereas Yin represents passive, negative, and inhibitory factors. In this review, we give a brief overview of history and latest progress about trained immunity, including experimental models, inductors, molecular mechanisms, clinical application and so on. Moreover, this is the first time to put forward the theory of Yin‐Yang balance to understand trained immunity. We envision that more efforts will be focused on developing novel immunotherapies targeting trained immunity in the coming years.

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“…After incubation, the medium was removed and the cells were washed with PBS (0.01 M, pH 7.40) before further studies. BV2 cells were pretreated with 100 nM rapamycin and 1 mM DMOG for 1 h before Hb incubation [23,24].…”

Section: Drug Administrationmentioning

confidence: 99%

Aerobic Glycolysis Induced by mTOR/HIF-1α Promotes Early Brain Injury After Subarachnoid Hemorrhage via Activating M1 Microglia

Sun

Chu

Godje

et al. 2022

Transl. Stroke Res.

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M1 microglial activation is crucial for the pathogenesis of early brain injury (EBI) following subarachnoid hemorrhage (SAH), and there is growing evidence that glucose metabolism is frequently involved in microglial activation. However, the molecular mechanism of glycolysis and its role in M1 microglial activation in context of EBI are not yet fully understood. In this study, rstly, the relationship between aerobic glycolysis and M1 microglial activation as well as SAH-induced EBI was researched in vivo. Then, intervention on mammalian target of rapamycin (mTOR) was performed to investigate the effects on glycolysis-dependent M1 microglial activation and EBI, and its relationship with hypoxia-inducible factor-1α (HIF-1α) in vivo. Next, Hif-1α was inhibited to analyze its role in aerobic glycolysis, M1 microglial activation and EBI in vivo. Lastly, both in vivo and in vitro, mTOR inhibition and Hif-1α enhancement were administered simultaneously, and the combined effects were further con rmed again. The results showed that aerobic glycolysis and M1 microglial polarization were increased after SAH, and glycolytic inhibition could attenuate M1 microglial activation and EBI. Inhibition of mTOR reduced glycolysis-dependent M1 microglial polarization and EBI severity by down-regulating HIF-1α expression, while enhancement had the opposite effects. Blockading HIF-1α had the similar effects as suppressing mTOR, while HIF-1α agonist worked against mTOR antagonist when administered simultaneously. In conclusion, the present study showed new evidence that aerobic glycolysis induced by mTOR/HIF-1α might promote EBI after SAH by activating M1 microglia. This nding provided new insights for the treatment of EBI.

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Rapamycin Modulates the Proinflammatory Memory-Like Response of Microglia Induced by BAFF

Cited by 11 publications

References 45 publications

Polymorphonuclear myeloid-derived suppressor cells play a proinflammatory role via TNF-α + B cells through BAFF/BTK/NF-B signaling pathway in the pathogenesis of collagen-induced arthritis mice

Polymorphonuclear myeloid-derived suppressor cells play a proinflammatory role via TNF-α + B cells through BAFF/BTK/NF-B signaling pathway in the pathogenesis of collagen-induced arthritis mice

Trained immunity: A Yin‐Yang balance

Aerobic Glycolysis Induced by mTOR/HIF-1α Promotes Early Brain Injury After Subarachnoid Hemorrhage via Activating M1 Microglia

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