Exosomal cargo including microRNA regulates sensory neuron to macrophage communication after nerve trauma

Simeoli, Raffaele; Montague, Karli; Jones, Hefin; Castaldi, Laura; Chambers, David; Kelleher, Jayne H.; Vacca, Valentina; Pitcher, Thomas; Grist, John; Alahdal, Hadil; Wong, Liang Fong; Perretti, Mauro; Lai, Johnathan C.; Mouritzen, Peter; Heppenstall, Paul A.; Malcangio, Marzia

doi:10.1038/s41467-017-01841-5

Cited by 224 publications

(174 citation statements)

References 43 publications

(52 reference statements)

Supporting

Mentioning

164

Contrasting

Order By: Relevance

“…A lower Cldn5 expression could significantly impact the function of the BDB, making it even more permeable for potentially harmful substances and immune cell invasion. Indeed, we confirmed increased invasion of macrophages in our model in the ipsilateral DRG after CCI, as shown previously in rats [22] and mice [23]. To evaluate possible BDB breakdown regarding permeability for small and large molecules, we performed a perfusion assay with FITC-dextran and Hoechst reagent as representative molecules with high and low molecular weights.…”

Section: Discussionsupporting

confidence: 87%

See 1 more Smart Citation

Regional Differences in Tight Junction Protein Expression in the Blood–DRG Barrier and Their Alterations after Nerve Traumatic Injury in Rats

Ben-Kraiem

Blum

et al. 2019

IJMS

View full text Add to dashboard Cite

The nervous system is shielded by special barriers. Nerve injury results in blood–nerve barrier breakdown with downregulation of certain tight junction proteins accompanying the painful neuropathic phenotype. The dorsal root ganglion (DRG) consists of a neuron-rich region (NRR, somata of somatosensory and nociceptive neurons) and a fibre-rich region (FRR), and their putative epi-/perineurium (EPN). Here, we analysed blood–DRG barrier (BDB) properties in these physiologically distinct regions in Wistar rats after chronic constriction injury (CCI). Cldn5, Cldn12, and Tjp1 (rats) mRNA were downregulated 1 week after traumatic nerve injury. Claudin-1 immunoreactivity (IR) found in the EPN, claudin-19-IR in the FRR, and ZO-1-IR in FRR-EPN were unaltered after CCI. However, laser-assisted, vessel specific qPCR, and IR studies confirmed a significant loss of claudin-5 in the NRR. The NRR was three-times more permeable compared to the FRR for high and low molecular weight markers. NRR permeability was not further increased 1-week after CCI, but significantly more CD68+ macrophages had migrated into the NRR. In summary, NRR and FRR are different in naïve rats. Short-term traumatic nerve injury leaves the already highly permeable BDB in the NRR unaltered for small and large molecules. Claudin-5 is downregulated in the NRR. This could facilitate macrophage invasion, and thereby neuronal sensitisation and hyperalgesia. Targeting the stabilisation of claudin-5 in microvessels and the BDB barrier could be a future approach for neuropathic pain therapy.

show abstract

Section: Discussionsupporting

confidence: 87%

“…In addition to molecules, cells can migrate into the DRG. Macrophages reside in the DRG and further migrate into the DRG to shape an immune response in neuropathy [22,23]. So, opening of the BDB could facilitate these pathophysiological processes.…”

Section: Discussionmentioning

confidence: 99%

Regional Differences in Tight Junction Protein Expression in the Blood–DRG Barrier and Their Alterations after Nerve Traumatic Injury in Rats

Ben-Kraiem

Blum

et al. 2019

IJMS

View full text Add to dashboard Cite

show abstract

“…These miR-21 loaded vesicles are readily phagocytosed by macrophages inducing a pro-inflammatory phenotype. Moreover, intratecal delivery of an antagomir of miR-21 or its conditional deletion in sensory neurons lower neuropathic hypersensitivity and inflammatory macrophage recruitment to the DRG indicating that the induction of miR-21 expression and its release contributes to sensory neuron-macrophage communication after peripheral nerve damage [97].…”

Section: Mt Impact On the Nervous System And On Pain Reliefmentioning

confidence: 99%

Unraveling molecular determinants of manual therapy: an approach to integrative therapeutics for the treatment of fibromyalgia and CFS/ME

Espejo¹,

García-Escudero²,

Oltra³

2018

Preprint

View full text Add to dashboard Cite

Abstract:Application of protocols without parameter standardization and rigorous controls has led manual therapy (MT) and other physiotherapy approaches to controversial outcomes. Thus, there is an urgency to carefully define standard protocols that elevate physiotherapy treatments to rigorous scientific demands. One way this can be achieved is by studying gene expression and additional physiological changes that associate to particular, parameter-controlled, treatments in animal models and translating this knowledge to properly design objective, quantitatively-monitored clinical trials. Here, we propose a Molecular Physiotherapy Approach (MPTA), requiring multidisciplinary teams, to uncover the scientific reasons behind the numerous reports of MT that historically attribute benefits to these treatments. The review focuses in the identification of MT-induced physiological and molecular responses that could be used for the treatment of fibromyalgia (FM) and CFS/ME. The systemic effect associated to mechanical-load responses is considered of particular relevance as it suggests that defined, low-pain areas could be selected for treatments with overall benefits, an aspect that might result essential to treat FM. Additionally, MT can provide muscle conditioning to sedentary patients without demanding strenuous physical effort, detrimental for CFS/ME patients, placing MT as a real option for integrative medicine programs to treat FM and CFS/ME.

show abstract

“…Macrophages that reside in peripheral nerve tissue are different from microglia and or nonnervous residing macrophages 13,14 and can be programmed by sensory neurons 15 . We determined whether monocytes/macrophages that infiltrate the DRG had an inflammatory ('M1') -or resolution ('M2')-like phenotype.…”

Section: Main Textmentioning

confidence: 99%

Macrophages transfer mitochondria to sensory neurons to resolve inflammatory pain

Raoof

Vlist

Willemen

et al. 2020

Preprint

View full text Add to dashboard Cite

The current paradigm states that inflammatory pain passively resolves following the cessation of the inflammatory insult. Yet, in a substantial proportion of patients with inflammatory diseases, such as rheumatoid arthritis and inflammatory bowel disease, spontaneous or treatment-induced resolution of inflammation is not sufficient to resolve pain, resulting in chronic pain 1-5 . Mechanistic insight as how inflammatory pain is resolved is lacking.Here we show that macrophages actively control resolution of inflammatory pain remotely from the site of inflammation by transferring mitochondria to sensory neurons. During resolution of inflammatory pain in mice, M2-like macrophages infiltrate the dorsal root ganglia that contain the somata of sensory neurons, concurrent with the recovery of oxidative phosphorylation in sensory neurons. To resolve pain, macrophages transfer mitochondria to sensory neurons. This transfer requires expression of CD200 Receptor (CD200R) on macrophages and the noncanonical CD200R-ligand iSec1 on sensory neurons. Our data reveal a novel mechanism for active resolution of inflammatory pain and suggests a new direction for treatment of chronic pain.

show abstract

Exosomal cargo including microRNA regulates sensory neuron to macrophage communication after nerve trauma

Cited by 224 publications

References 43 publications

Regional Differences in Tight Junction Protein Expression in the Blood–DRG Barrier and Their Alterations after Nerve Traumatic Injury in Rats

Regional Differences in Tight Junction Protein Expression in the Blood–DRG Barrier and Their Alterations after Nerve Traumatic Injury in Rats

Unraveling molecular determinants of manual therapy: an approach to integrative therapeutics for the treatment of fibromyalgia and CFS/ME

Macrophages transfer mitochondria to sensory neurons to resolve inflammatory pain

Contact Info

Product

Resources

About