Microglia-mediated degradation of perineuronal nets promotes pain

Tansley, Shannon; Gu, Ning; Guzmán, Alba Ureña; Cai, Weihua; Wong, Calvin; Lister, Kevin C.; Muñoz-Pino, Einer; Yousefpour, Noosha; Roome, R. Brian; Heal, Jordyn; Wu, Neil; Castonguay, Annie; Lean, Graham; Muir, Elizabeth M.; Kania, Artur; Prager‐Khoutorsky, Masha; Ji, Zhang; Gkogkas, Christos G.; Fawcett, James W.; Diatchenko, Luda; Ribeiro‐da‐Silva, Alfredo; Koninck, Yves De; Mogil, Jeffrey S.; Khoutorsky, Arkady

doi:10.1126/science.abl6773

Cited by 102 publications

(59 citation statements)

References 44 publications

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“…Activated microglia may promote central disinhibition by selectively phagocytosing inhibitory synaptic terminals [ 84 ] or displacing inhibitory axosomatic presynaptic terminals from cortical neurons [ 85 ]; moreover, blocking microglial activation alleviates PV-IN dysfunction and behavioral changes caused by inflammation or brain injury [ 82 , 83 , 86 ]. In addition, activated microglia may also interfere with the activity of inhibitory synapses by degrading perineuronal nets (PNNs) [ 87 , 88 ], a specialized extracellular matrix structure enwrapping cortical inhibitory fast-spiking PV-INs [ 89 , 90 ]. Our recent work demonstrated that SNI induces the activation of microglia, but not astrocytes, in the bilateral ACC [ 34 , 45 ].…”

Section: Discussionmentioning

confidence: 99%

NLRP3-Mediated Piezo1 Upregulation in ACC Inhibitory Parvalbumin-Expressing Interneurons Is Involved in Pain Processing after Peripheral Nerve Injury

Duan²,

Yao-hui³

et al. 2022

IJMS

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The anterior cingulate cortex (ACC) is particularly critical for pain information processing. Peripheral nerve injury triggers neuronal hyper-excitability in the ACC and mediates descending facilitation to the spinal dorsal horn. The mechanically gated ion channel Piezo1 is involved in the transmission of pain information in the peripheral nervous system. However, the pain-processing role of Piezo1 in the brain is unknown. In this work, we found that spared (sciatic) nerve injury (SNI) increased Piezo1 protein levels in inhibitory parvalbumin (PV)-expressing interneurons (PV-INs) but not in glutaminergic CaMKⅡ+ neurons, in the bilateral ACC. A reduction in the number of PV-INs but not in the number of CaMKⅡ+ neurons and a significant reduction in inhibitory synaptic terminals was observed in the SNI chronic pain model. Further, observation of morphological changes in the microglia in the ACC showed their activated amoeba-like transformation, with a reduction in process length and an increase in cell body area. Combined with the encapsulation of Piezo1-positive neurons by Iba1+ microglia, the loss of PV-INs after SNI might result from phagocytosis by the microglia. In cellular experiments, administration of recombinant rat TNF-α (rrTNF) to the BV2 cell culture or ACC neuron primary culture elevated the protein levels of Piezo1 and NOD-like receptor (NLR) family pyrin domain containing 3 (NLRP3). The administration of the NLRP3 inhibitor MCC950 in these cells blocked the rrTNF-induced expression of caspase-1 and interleukin-1β (key downstream factors of the activated NLRP3 inflammasome) in vitro and reversed the SNI-induced Piezo1 overexpression in the ACC and alleviated SNI-induced allodynia in vivo. These results suggest that NLRP3 may be the key factor in causing Piezo1 upregulation in SNI, promoting an imbalance between ACC excitation and inhibition by inducing the microglial phagocytosis of PV-INs and, thereby, facilitating spinal pain transmission.

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Section: Discussionmentioning

confidence: 99%

NLRP3-Mediated Piezo1 Upregulation in ACC Inhibitory Parvalbumin-Expressing Interneurons Is Involved in Pain Processing after Peripheral Nerve Injury

Duan²,

Yao-hui³

et al. 2022

IJMS

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“…Experimental disruption of PNNs mimics the increased capacitance and reduced firing activity of PV neurons as shown by PV neurons with disrupted PNNs in glioma ( Tewari et al, 2018 ), suggesting a pivotal role of PNNs in aiding the fast-spiking properties of PV neurons. PNNs seem to determine the activity of excitatory neurons equally well, as evidenced in a recent study in which microglia-mediated degradation of PNNs around excitatory projection neurons in the spinal cord enhances their activity and induces pain-related behavior ( Tansley et al, 2022 ). Another example is the induction of synaptic plasticity in CA2 neurons upon their PNN depletion, which are otherwise resistant to potentiation ( Carstens et al, 2016 ).…”

Section: Functions Of Perineuronal Netsmentioning

confidence: 91%

“…A similar role of microglia has recently been reported in the spinal cord dorsal horn wherein peripheral nerve injury promotes microglial degradation and endocytosis of PNNs around projection neurons. PNN depletion activates the projection neurons to induce pain-related behavior ( Tansley et al, 2022 ). Despite such explicit presentations of microglial involvement, what triggers microglia to start stripping PNNs and ECM components with or without proteolytic cleavage is still an open question.…”

Section: Extracellular Matrix and Perineuronal Net Remodeling By Micr...mentioning

confidence: 99%

“…Normally, the homeostatic states of ECM and PNNs are maintained by a constitutive expression of ECM and proteases by neurons and astrocytes, as well as clearance by microglia. However, as seen in several recent studies on epilepsy, Alzheimer’s disease (AD), Huntington’s disease (HD), neuropathic pain, etc., dysfunctional microglia leads to abnormal clearance or accumulation of the ECM and PNNs contributing to the pathology ( Tewari et al, 2018 ; Patel et al, 2019 ; Crapser et al, 2020b , 2021 ; Chaunsali et al, 2021 ; Carceller et al, 2022 ; Tansley et al, 2022 ).…”

Section: Introductionmentioning

confidence: 99%

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A glial perspective on the extracellular matrix and perineuronal net remodeling in the central nervous system

Tewari

Chaunsali

Prim

et al. 2022

Front. Cell. Neurosci.

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A structural scaffold embedding brain cells and vasculature is known as extracellular matrix (ECM). The physical appearance of ECM in the central nervous system (CNS) ranges from a diffused, homogeneous, amorphous, and nearly omnipresent matrix to highly organized distinct morphologies such as basement membranes and perineuronal nets (PNNs). ECM changes its composition and organization during development, adulthood, aging, and in several CNS pathologies. This spatiotemporal dynamic nature of the ECM and PNNs brings a unique versatility to their functions spanning from neurogenesis, cell migration and differentiation, axonal growth, and pathfinding cues, etc., in the developing brain, to stabilizing synapses, neuromodulation, and being an active partner of tetrapartite synapses in the adult brain. The malleability of ECM and PNNs is governed by both intrinsic and extrinsic factors. Glial cells are among the major extrinsic factors that facilitate the remodeling of ECM and PNN, thereby acting as key regulators of diverse functions of ECM and PNN in health and diseases. In this review, we discuss recent advances in our understanding of PNNs and how glial cells are central to ECM and PNN remodeling in normal and pathological states of the CNS.

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“…Hyper NETosis or ineffective clearance of NETs would likely contribute to the pathogenesis of immune-related diseases ( 8 ). NETs are involved in numerous pathological processes, including infection ( 9 ), autoimmune diseases ( 10 ), tumor development ( 11 ), Alzheimer’s disease ( 12 ), acute ischemic stroke ( 13 ), peripheral nerve injury ( 14 ) and thrombosis ( 8 ). However, its role in neuroimmune diseases remains unclear.…”

Section: Introductionmentioning

confidence: 99%

Increased formation of neutrophil extracellular traps in patients with anti-N-methyl-d-aspartate receptor encephalitis

et al. 2022

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BackgroundNeutrophil extracellular traps (NETs) have been found to play an important role in several nervous system diseases. However, their role in anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis remains unclear. The purpose of this study was to examine the possible role of NETs in anti-NMDAR encephalitis.Materials and methodsEleven patients with anti-NMDAR encephalitis and ten healthy participants were enrolled. Plasma NETs levels were detected using an immunofluorescence assay and enzyme-linked immunosorbent assay. Additionally, we examined 10 plasma cytokines in patients with anti-NMDAR encephalitis and analyzed the correlation between citrullinated histone 3 levels and cytokine release. ResultsPeripheral blood neutrophils from patients with anti-NMDAR encephalitis were more susceptible to NET generation. When compared with controls, cases of anti-NMDAR encephalitis showed elevated levels of IL-1 α, IL-6, IL-8, IL-13, MCP-1, and TNF-α (p < 0.05). Moreover, IL-6, IL-8, and TNF-α levels were positively correlated with H3Cit levels.ConclusionWe provide evidence that NETs may play a role in anti-NMDAR encephalitis, providing clues for elucidation of the pathogenesis of this disease.

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Microglia-mediated degradation of perineuronal nets promotes pain

Cited by 102 publications

References 44 publications

NLRP3-Mediated Piezo1 Upregulation in ACC Inhibitory Parvalbumin-Expressing Interneurons Is Involved in Pain Processing after Peripheral Nerve Injury

NLRP3-Mediated Piezo1 Upregulation in ACC Inhibitory Parvalbumin-Expressing Interneurons Is Involved in Pain Processing after Peripheral Nerve Injury

A glial perspective on the extracellular matrix and perineuronal net remodeling in the central nervous system

Increased formation of neutrophil extracellular traps in patients with anti-N-methyl-d-aspartate receptor encephalitis

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