Macrophages transfer mitochondria to sensory neurons to resolve inflammatory pain

Vlist, Michiel van der; Raoof, Ramin; Willemen, Hanneke L.D.M.; Prado, Judith; Versteeg, Sabine; Gil, Christian Martin; Vos, Martijn; Lokhorst, Roeland E; Pasterkamp, R. Jeroen; Kojima, Toshiyuki; Karasuyama, Hajime; Khoury-Hanold, William; Meyaard, Linde; Eijkelkamp, Niels

doi:10.1016/j.neuron.2021.11.020

Cited by 123 publications

(83 citation statements)

References 93 publications

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“…Recent evidence also suggests that CD200R1 can engage ligands other than CD200, such as iSEC1 and iSEC2 [ 39 , 40 ], generating more challenging conditions to unravel the function of this immune receptor. The expression of iSEC1 and iSEC2 were initially described as being restricted to epithelial cells of the digestive tract [ 39 ] and just very recently iSEC1 mRNA has been shown to be expressed by sensory neurons of the dorsal root ganglia [ 40 ] and in some endothelial cells [ 30 ]. It was reported to be involved in the transport of mitochondria from macrophages to neurons [ 40 ].…”

Section: Discussionmentioning

confidence: 99%

“…The expression of iSEC1 and iSEC2 were initially described as being restricted to epithelial cells of the digestive tract [ 39 ] and just very recently iSEC1 mRNA has been shown to be expressed by sensory neurons of the dorsal root ganglia [ 40 ] and in some endothelial cells [ 30 ]. It was reported to be involved in the transport of mitochondria from macrophages to neurons [ 40 ]. This fact could suggest that problems in the transport of mitochondria by blocking CD200R1 could lead to a failed energy boost needed by axons after nerve injury and thus lead to problems in conduction velocity that could result in the impaired locomotor function recovery.…”

Section: Discussionmentioning

confidence: 99%

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CD200R1 Contributes to Successful Functional Reinnervation after a Sciatic Nerve Injury

Pannunzio

Amo-Aparicio

Julián

et al. 2022

Cells

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Activating and inhibitory immune receptors play a critical role in regulating systemic and central nervous system (CNS) immune and inflammatory processes. The CD200R1 immunoreceptor induces a restraining signal modulating inflammation and phagocytosis in the CNS under different inflammatory conditions. However, it remains unknown whether CD200R1 has a role in modulating the inflammatory response after a peripheral nerve injury, an essential component of the successful regeneration. Expression of CD200R1 and its ligand CD200 was analyzed during homeostasis and after a sciatic nerve crush injury in C57Bl/6 mice. The role of CD200R1 in Wallerian Degeneration (WD) and nerve regeneration was studied using a specific antibody against CD200R1 injected into the nerve at the time of injury. We found an upregulation of CD200R1 mRNA after injury whereas CD200 was downregulated acutely after nerve injury. Blockade of CD200R1 significantly reduced the acute entrance of both neutrophils and monocytes from blood after nerve injury. When long term regeneration and functional recovery were evaluated, we found that blockade of CD200R1 had a significant effect impairing the spontaneous functional recovery. Taken together, these results show that CD200R1 has a role in mounting a successful acute inflammatory reaction after injury, and contributes to an effective functional recovery.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

CD200R1 Contributes to Successful Functional Reinnervation after a Sciatic Nerve Injury

Pannunzio

Amo-Aparicio

Julián

et al. 2022

Cells

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“…Mitochondria-rich m/lEVs structures were consistent with published reports (31–34). Prior studies have demonstrated that mitochondria or mitochondrial components such as mtDNA, mitochondrial proteins were secreted into the extracellular milieu and transferred between cells (32, 34, 55–60). For instance, mesenchymal stem cell-derived-m/lEVs transferred mitochondria into the recipient macrophages leading to increased cellular bioenergetics (32).…”

Section: Discussionmentioning

confidence: 99%

Mitochondria-containing Extracellular Vesicles (EV) Reduce Mouse Brain Infarct Sizes and EV/HSP27 Protect Ischemic Brain Endothelial Cultures

Reynolds

et al. 2021

Preprint

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Ischemic stroke causes brain endothelial cell death and damages tight junction integrity of the blood-brain barrier (BBB). We engineered endothelial cell-derived extracellular vesicles (EVs) for the delivery of exogenous heat shock protein 27 (HSP27) and harnessed the innate EV mitochondrial load as a one, two-punch strategy to increase brain endothelial cell survival (via mitochondrial delivery) and preserve their tight junction integrity (via HSP27 delivery). We demonstrated that endothelial microvesicles but not exosomes transferred their mitochondrial load that subsequently underwent fusion with the mitochondrial network of the recipient primary human brain endothelial cells. This mitochondrial transfer increased the relative ATP levels and mitochondrial function in the recipient endothelial cells. EV-mediated HSP27 delivery to primary human brain endothelial cells decreased the paracellular permeability of small and large molecular mass fluorescent tracers in an in vitro model of ischemia/reperfusion injury. This one, two-punch approach to increase the metabolic function and structural integrity of brain endothelial cells is a promising strategy for BBB protection and prevention of long-term neurological dysfunction post-ischemic stroke.Highlights➢Exosomes and microvesicles (EVs) can be engineered for co-delivery of bio-actives➢Microvesicles (MV) but not exosomes contain functional mitochondria➢MV mitochondria fused with the mitochondria in recipient brain endothelial cells➢MVs increase mitochondrial function while EVs increase cellular ATP levels➢EV-mediated HSP27 delivery decreased dextran permeability in brain endothelial cellsGraphical Abstract

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“…However, whether inhibition of Nox2 might have a therapeutic potential in the treatment of neuropathic pain or other pain conditions needs to be elucidated in further studies. Nonetheless, one also has to consider the fact that Nox2-dependent superoxide production is essential for an appropriate host defense and that it plays a critical role in the resolution of inflammation [ 49 , 60 , 96 , 97 , 98 , 99 ]. Hence, Nox2-inhibiting therapeutic strategies might be associated with various unwanted side effects.…”

Section: Nadph Oxidases Affect Pain Processing By Distinct Mechanismsmentioning

confidence: 99%

NADPH Oxidases in Pain Processing

2022

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Inflammation or injury to the somatosensory nervous system may result in chronic pain conditions, which affect millions of people and often cause major health problems. Emerging lines of evidence indicate that reactive oxygen species (ROS), such as superoxide anion or hydrogen peroxide, are produced in the nociceptive system during chronic inflammatory and neuropathic pain and act as specific signaling molecules in pain processing. Among potential ROS sources in the somatosensory system are NADPH oxidases, a group of electron-transporting transmembrane enzymes whose sole function seems to be the generation of ROS. Interestingly, the expression and relevant function of the Nox family members Nox1, Nox2, and Nox4 in various cells of the nociceptive system have been demonstrated. Studies using knockout mice or specific knockdown of these isoforms indicate that Nox1, Nox2, and Nox4 specifically contribute to distinct signaling pathways in chronic inflammatory and/or neuropathic pain states. As selective Nox inhibitors are currently being developed and investigated in various physiological and pathophysiological settings, targeting Nox1, Nox2, and/or Nox4 could be a novel strategy for the treatment of chronic pain. Here, we summarize the distinct roles of Nox1, Nox2, and Nox4 in inflammatory and neuropathic processing and discuss the effectiveness of currently available Nox inhibitors in the treatment of chronic pain conditions.

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Macrophages transfer mitochondria to sensory neurons to resolve inflammatory pain

Cited by 123 publications

References 93 publications

CD200R1 Contributes to Successful Functional Reinnervation after a Sciatic Nerve Injury

CD200R1 Contributes to Successful Functional Reinnervation after a Sciatic Nerve Injury

Mitochondria-containing Extracellular Vesicles (EV) Reduce Mouse Brain Infarct Sizes and EV/HSP27 Protect Ischemic Brain Endothelial Cultures

NADPH Oxidases in Pain Processing

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