Osteoprotegerin mediate RANK/RANKL signaling inhibition eases asthma inflammatory reaction by affecting the survival and function of dendritic cells

Yang, Xia; Wang, X.; Chi, Michael; Zhang, M.; Huang, Shan; Zhang, Q.-H.; Zhang, J.; Shi, Junnan; Zhang, J.-Z.; Wu, Runmiao; Li, Y.-L.

doi:10.1016/j.aller.2018.06.006

Cited by 9 publications

(5 citation statements)

References 34 publications

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“…In fact, dendritic cells from OPG −/− mice produce higher levels of inflammatory cytokines in vitro and in vivo upon LPS treatment [ 17 ] and are more effective in driving T cell responses [ 81 ]. Conversely, OPG administration ameliorates intestinal inflammation and mucosal dendritic cell infiltration [ 3 ], while OPG overexpression reduces dendritic cell activation in an asthma model [ 79 ]. Our data show that OPG downregulation is at least one of the factors leading to increased microglial reactivity when neuronal NC signaling is inhibited, since re-establishing OPG expression normalized microglial response to mild TBI and prevented the excessive loss of synapses.…”

Section: Discussionmentioning

confidence: 99%

Neuronal nuclear calcium signaling suppression of microglial reactivity is mediated by osteoprotegerin after traumatic brain injury

Frohlich

Heuvel

Rehman

et al. 2022

J Neuroinflammation

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Background Traumatic brain injury (TBI) is characterized by massive changes in neuronal excitation, from acute excitotoxicity to chronic hyper- or hypoexcitability. Nuclear calcium signaling pathways are involved in translating changes in synaptic inputs and neuronal activity into discrete transcriptional programs which not only affect neuronal survival and synaptic integrity, but also the crosstalk between neurons and glial cells. Here, we report the effects of blunting neuronal nuclear calcium signals in the context of TBI. Methods We used AAV vectors to express the genetically encoded and nuclear-targeted calcium buffer parvalbumin (PV.NLS.mCherry) or the calcium/calmodulin buffer CaMBP4.mCherry in neurons only. Upon TBI, the extent of neuroinflammation, neuronal death and synaptic loss were assessed by immunohistochemistry and targeted transcriptome analysis. Modulation of the overall level of neuronal activity was achieved by PSAM/PSEM chemogenetics targeted to parvalbumin interneurons. The functional impact of neuronal nuclear calcium buffering in TBI was assessed by quantification of spontaneous whisking. Results Buffering neuronal nuclear calcium unexpectedly resulted in a massive and long-lasting increase in the recruitment of reactive microglia to the injury site, which was characterized by a disease-associated and phagocytic phenotype. This effect was accompanied by a substantial surge in synaptic loss and significantly reduced whisking activity. Transcriptome analysis revealed a complex effect of TBI in the context of neuronal nuclear calcium buffering, with upregulation of complement factors, chemokines and interferon-response genes, as well as the downregulation of synaptic genes and epigenetic regulators compared to control conditions. Notably, nuclear calcium buffering led to a substantial loss in neuronal osteoprotegerin (OPG), whereas stimulation of neuronal firing induced OPG expression. Viral re-expression of OPG resulted in decreased microglial recruitment and synaptic loss. OPG upregulation was also observed in the CSF of human TBI patients, underscoring its translational value. Conclusion Neuronal nuclear calcium signals regulate the degree of microglial recruitment and reactivity upon TBI via, among others, osteoprotegerin signals. Our findings support a model whereby neuronal activity altered after TBI exerts a powerful impact on the neuroinflammatory cascade, which in turn contributes to the overall loss of synapses and functional impairment.

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Section: Discussionmentioning

confidence: 99%

Neuronal nuclear calcium signaling suppression of microglial reactivity is mediated by osteoprotegerin after traumatic brain injury

Frohlich

Heuvel

Rehman

et al. 2022

J Neuroinflammation

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“…In fact, dendritic cells from OPG -/- mice produce higher levels of inflammatory cytokines in vitro and in vivo upon LPS treatment (Chino et al, 2009) and are more effective in driving T-cell responses (Yun et al, 2001). Conversely, OPG administration ameliorates intestinal inflammation and mucosal dendritic cells infiltration (Ashcroft et al, 2003), while OPG overexpression reduces dendritic cell activation in an asthma model (Yang et al, 2019). Our data show that OPG downregulation is at least one of the factors leading to increased microglial reactivity when neuronal NC signaling is inhibited, since re-establishing OPG expression normalized microglial response to mild TBI and prevented the excessive loss of synapses.…”

Section: Discussionmentioning

confidence: 99%

Neuronal nuclear calcium signaling suppression of microglial reactivity is mediated by osteoprotegerin after traumatic brain injury

Froehlich

Heuvel

Rehman

et al. 2022

Preprint

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BackgroundTraumatic Brain Injury (TBI) is characterized by massive changes in neuronal excitation, from acute excitotoxicity to chronic hyper- or hypoexcitability. Nuclear calcium signaling pathways are involved in translating changes in synaptic inputs and neuronal activity into discrete transcriptional programs which not only affect neuronal survival and synaptic integrity, but also the crosstalk between neurons and glial cells. Here we report the effects of blunting neuronal nuclear calcium signals in the context of TBI.MethodsWe used AAV vectors to express the genetically-encoded and nuclear-targeted calcium buffer parvalbumin (PV.NLS.mCherry) or the calcium/calmodulin buffer CaMBP4.mCherry in neurons only. Upon TBI, the extent of neuroinflammation, neuronal death and synaptic loss were assessed by immunohistochemistry and targeted transcriptome analysis. Modulation of the overall level of neuronal activity was achieved by PSAM/PSEM chemogenetics targeted to parvalbumin interneurons. The functional impact of neuronal nuclear Calcium buffering in TBI was assessed by quantification of spontaneous whisking.ResultsBuffering neuronal nuclear calcium unexpectedly resulted in a massive and long-lasting increase in the recruitment of reactive microglia to the injury site, which was characterised by a disease-associated and phagocytic phenotypes. This effect was accompanied by a substantial surge in synaptic loss and significantly reduced whisking activity. Transcriptome analysis revealed a complex effect of TBI in the context of neuronal nuclear calcium buffering, with upregulation of complement factors, chemokines and interferon-response genes, as well as the downregulation of synaptic genes and epigenetic regulators compared to control conditions. Notably, nuclear calcium buffering led to a substantial loss in neuronal osteoprotegerin (OPG). Whereas stimulation of neuronal firing induced OPG expression. Viral re-expression of OPG resulted in decreased microglial recruitment and synaptic loss. OPG upregulation was also observed in the CSF of human TBI patients, underscoring its translational value.ConclusionNeuronal nuclear calcium signals regulate the degree of microglial recruitment and reactivity upon TBI via, among others, osteoprotegerin signals. Our findings support a model whereby neuronal activity altered after TBI exerts a powerful impact on the neuroinflammatory cascade, which in turn contributes to the overall loss of synapses and functional impairment.

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“…More specifically, RANKL expression on T cells acts to induce survival and maturation of dendritic cells. A murine study has shown that OVA-induced airway inflammatory responses are reversed in the presence of OPG, suggesting that the blockade of the RANKL–RANK axis plays a role in asthma inflammation [ 86 ]. Another study also has shown that blockade of the RANKL–RANK axis results in attenuation of allergic airway inflammation in mice [ 87 ].…”

Section: Relationship Between Tnf Superfamily and Ilc2mentioning

confidence: 99%

TNF Superfamily and ILC2 Activation in Asthma

Matsuyama,

Salter,

Emami Fard

et al. 2024

Biomolecules

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Eosinophilic asthma is the most prevalent and well-defined phenotype of asthma. Despite a majority of patients responding to corticosteroid therapy and T2 biologics, there remains a subset that have recurrent asthma exacerbations, highlighting a need for additional therapies to fully ameliorate airway eosinophilia. Group 2 innate lymphoid cells (ILC2) are considered key players in the pathogenesis of eosinophilic asthma through the production of copious amounts of type 2 cytokines, namely IL-5 and IL-13. ILC2 numbers are increased in the airways of asthmatics and with the greatest numbers of activated ILC2 detected in sputa from severe prednisone-dependent asthma with uncontrolled eosinophilia. Although epithelial-derived cytokines are important mediators of ILC2 activation, emerging evidence suggests that additional pathways stimulate ILC2 function. The tumor necrosis factor super family (TNFSF) and its receptors (TNFRSF) promote ILC2 activity. In this review, we discuss evidence supporting a relationship between ILC2 and TNFSF/TNFRSF axis in eosinophilic asthma and the role of this relationship in severe asthma with airway autoimmune responses.

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Osteoprotegerin mediate RANK/RANKL signaling inhibition eases asthma inflammatory reaction by affecting the survival and function of dendritic cells

Cited by 9 publications

References 34 publications

Neuronal nuclear calcium signaling suppression of microglial reactivity is mediated by osteoprotegerin after traumatic brain injury

Neuronal nuclear calcium signaling suppression of microglial reactivity is mediated by osteoprotegerin after traumatic brain injury

Neuronal nuclear calcium signaling suppression of microglial reactivity is mediated by osteoprotegerin after traumatic brain injury

TNF Superfamily and ILC2 Activation in Asthma

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