Trigeminal neurons control immune-bone cell interaction and metabolism in apical periodontitis

Austah, Obadah; Lillis, Katherine V.; Akopian, Armen N.; Harris, S. E.; Grinceviciute, Ruta; Diogenes, Aníbal

doi:10.1007/s00018-022-04335-w

Cited by 10 publications

(19 citation statements)

References 61 publications

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“…Transgenic rats with interleukin-6 overexpression have bone loss and increased bone absorption [ 31 ]. Recently, according to relevant literature, IL-6 promotes bone resorption by inducing the proliferation of osteoclasts along the RANKL/RANK/OPG axis [ 32 ]. IL-6 can raise the expression of RANKL in osteoblasts [ 33 ].…”

Section: Discussionmentioning

confidence: 99%

Efficacy and Mechanisms of Oleuropein in Postmenopausal Osteoporosis

Liu

Zhao

Huang

et al. 2022

Computational and Mathematical Methods in Medicine

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Background. Postmenopausal osteoporosis (PMOP) has a supernal morbidity rate in elderly females. Objective. To appraise the effects of oleuropein on bone densitometry, bone metabolic index, oxidative stress, and inflammatory index in PMOP. In addition, the mechanism of olive bittersweet preventing bone loss was explored. Methods. We grouped 80 salubrious female Sprague-Dawley rats into four teams: (1) sham operation team (sham, N = 20 ), (2) ovariectomy (OVX, N = 20 ), (3) castrated mice fed with oleuropein (OVX+ole, N = 20 ), and (4) castrated mice fed with estrogen (OVX+E2, N = 20 ). The ovariectomized SD rats were continuously raised with 200 μg/kg/dose of oleuropein. Bone mineral density and bone metabolism indexes were recorded. In order to assess the effectiveness of oleuropein on osteopenia, an enzyme-linked immunosorbent assay (ELISA) was devoted to examining the bone marrow indexes. The bone metabolism standards of PMOP rats were appraised by assessing serum levels of calcium, alkaline phosphatase (ALP), phosphorus, malondialdehyde (MDA), and nitrate content by experimental detection methods and levels of osteoclastogenesis inhibitory factor (OPG) and receptor activator for nuclear factor-κB ligand (RANKL) by ELISA. The OPG-RANK-RANKL signal passage was examined by Western blot (WB). We measured bone mineral density using dual-energy X-rays. Results. Our animal experimental results indicated that oleuropein could significantly improve the bone mineral density of ovariectomized SD rats. In the meantime, it could reduce ending interleukin-6 (IL-6), malondialdehyde (MDA), nitrate, alkaline phosphatase (ALP), and phosphorus (P) serum concentration and would not affect Ca2+ concentration. In cell experiments, oleuropein also can promote the proliferation of osteoblasts. Furthermore, it can promote the expression of OPG protein and mRNA. In reverse, it inhibits the expression of RANKL protein and mRNA. Conclusion. Oleuropein can not only improve the inflammatory and oxidative indexes of castrated rats but also prevent osteoporosis. Oleuropein avoids bone resorption by regulating OPG/RANKL expression.

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Section: Discussionmentioning

confidence: 99%

Efficacy and Mechanisms of Oleuropein in Postmenopausal Osteoporosis

Liu

Zhao

Huang

et al. 2022

Computational and Mathematical Methods in Medicine

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“…CD68 has been indicated as a marker of all the activated macrophages in the sensory ganglion. 27 The results showed that CFA administration significantly increase the number of macrophages (compared to the saline control, P < 0.0001). Sympathectomy markedly reduced the number of macrophages infiltrated in the TG after the induction of orofacial inflammation (105.7 ± 7.4 in SYM group versus 138.1 ± 5.7 in CFA group, P < 0.01, Figure 2A and B ).…”

Section: Resultsmentioning

confidence: 91%

Sympathectomy Ameliorates CFA-Induced Mechanical Allodynia via Modulating Phenotype of Macrophages in Sensory Ganglion in Mice

Mai¹,

Jia²,

Liu³

et al. 2022

JIR

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Background The sympathetic nervous system (SNS) is suggested to be involved in some forms of pain, but the mechanisms of which are incompletely known. Moreover, there is a lack of information on the regulatory role of the SNS on macrophages in sensory ganglion, which plays an important role in pain development. The present study aims to investigate the effects of the SNS on orofacial inflammatory pain and examine, if any, how the SNS influences trigeminal ganglion (TG) macrophage responses. Methods Sympathectomy was performed on male C57BL/6 mice before receiving a local injection of Complete Freund’s adjuvant (CFA) to induce inflammatory pain. Effects of sympathectomy on orofacial pain were examined by Von Frey test and c-Fos expression. Polarization of TG macrophage was evaluated by immunohistochemistry and the level of norepinephrine (NE) in the TG were determined by liquid chromatography. Sympathetic signaling to TG macrophages were predicted based on single-cell analysis. Results CFA injection induced a significant increase in mechanical allodynia, the number of c-Fos-positive neuron, and the level of NE in TG, which were largely reduced by sympathectomy. The number of M1 macrophages was markedly increased by CFA and was largely reduced by sympathectomy from 1 to 14 days post-injection. Single-cell RNA sequencing analysis and immunofluorescence staining showed that TG macrophages mainly express β2 adrenergic receptors for NE. Cell–cell communication analysis predicted sympathetic signaling that may modulate macrophage phenotypes, including Colony-stimulating factor-1, Migration inhibitory factor, Pleiotrophin and Nicotinamide phosphoribosyl transferase. Conclusion The SNS may involve in CFA-induced mechanical allodynia via modulating macrophage phenotypes in the TG. Targeting sympathetic activation might be useful in treating some painful conditions in the orofacial region.

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“…We found that nociceptor ablation results in an earlier increase in inflammation, as shown by the upregulation of key cytokines and a greater influx of macrophages and lymphocytes. In addition, we have shown that nociceptors directly regulate osteoblastic and osteoclastic functions, demonstrating direct communication with bone metabolism cells 8 . While the progression of AP inflammatory responses had been previously characterized 13 , the overall transcriptomic profiling of this process and its regulation by nociceptors is unknown.…”

Section: Introductionmentioning

confidence: 94%

“…As such, we have recently shown that in a rodent model of apical periodontitis (AP), nociceptors are osteoprotective by attenuating bone loss after infection when compared to nociceptor-ablated rodents 8 , 9 . We found that nociceptor ablation results in an earlier increase in inflammation, as shown by the upregulation of key cytokines and a greater influx of macrophages and lymphocytes.…”

Section: Introductionmentioning

confidence: 99%

Nociceptors regulate osteoimmune transcriptomic response to infection

Lillis,

Austah,

Grinceviciute

et al. 2023

Sci Rep

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Osteoimmune diseases, such as apical periodontitis, are prevalent, often painful, inflammatory conditions resulting in bone loss and reduced quality of life. There is growing evidence that the nociceptive fibers densely innervating affected tissues regulate disease progression; therefore, we hypothesized that nociceptors regulate the transcriptomic profile of the periapical osteolytic lesion in a mouse model of apical periodontitis. Male control and nociceptor-ablated mice underwent pulp exposures, and after 0, 7, or 14 days, total RNA from periapical tissues was submitted for sequencing and bioinformatic analysis. Pulp exposure triggers the differential expression of hundreds of genes over the course of infection. At 14 days post pulp exposure, 422 genes, including Tnf, Il1a, and Il1b, were differentially expressed between nociceptor-ablated and control mice with greater enrichment of biological processes related to inflammation in nociceptor-ablated mice. Nociceptor ablation regulates the transcriptomic profile of periapical lesions in a mouse model of apical periodontitis, shifting the gene expression profile to a greater enrichment of inflammatory genes, suggesting nociceptors play a role in the kinetics of the immune response. This newly uncovered neuro-immune axis and its mechanisms in apical periodontitis can be an important therapeutic target for the treatment of this prevalent disease.

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Trigeminal neurons control immune-bone cell interaction and metabolism in apical periodontitis

Cited by 10 publications

References 61 publications

Efficacy and Mechanisms of Oleuropein in Postmenopausal Osteoporosis

Efficacy and Mechanisms of Oleuropein in Postmenopausal Osteoporosis

Sympathectomy Ameliorates CFA-Induced Mechanical Allodynia via Modulating Phenotype of Macrophages in Sensory Ganglion in Mice

Nociceptors regulate osteoimmune transcriptomic response to infection

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