Transplantation of M2-Deviated Microglia Promotes Recovery of Motor Function after Spinal Cord Injury in Mice

Kobashi, Shuhei; Terashima, Tomoya; Katagi, Munehiro; Nakae, Yuki; Okano, Jun-ichi; Suzuki, Yoshihisa; Urushitani, Makoto; Kojima, Hideto

doi:10.1016/j.ymthe.2019.09.004

Cited by 136 publications

(100 citation statements)

References 69 publications

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“…Finding therapeutic modalities that ameliorate autophagic reduction, or ones that can be targeted away from neurons, is crucial. In conditions of trauma such as spinal cord injury that are accompanied by elevated ATP and autophagic dysregulation (Galluzzi et al, 2016 ; Li et al, 2019 ), the modulation of microglial activation state has been proposed to enhance repair (Hu et al, 2015 ; Akhmetzyanova et al, 2019 ; Kobashi et al, 2020 ). However, treatment timing is critical, as transient P2X 7 receptor stimulation may enhance autophagy and promote M2a microglia, while sustained stimulation can inhibit autophagy and promote proinflammatory M1 microglia (Fabbrizio et al, 2017 ; Jiang et al, 2021 ).…”

Section: Discussionmentioning

confidence: 99%

The P2X7 Receptor in Microglial Cells Modulates the Endolysosomal Axis, Autophagy, and Phagocytosis

Campagno

Mitchell

2021

Front. Cell. Neurosci.

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Microglial cells regulate neural homeostasis by coordinating both immune responses and clearance of debris, and the P2X7 receptor for extracellular ATP plays a central role in both functions. The P2X7 receptor is primarily known in microglial cells for its immune signaling and NLRP3 inflammasome activation. However, the receptor also affects the clearance of extracellular and intracellular debris through modifications of lysosomal function, phagocytosis, and autophagy. In the absence of an agonist, the P2X7 receptor acts as a scavenger receptor to phagocytose material. Transient receptor stimulation induces autophagy and increases LC3-II levels, likely through calcium-dependent phosphorylation of AMPK, and activates microglia to an M1 or mixed M1/M2 state. We show an increased expression of Nos2 and Tnfa and a decreased expression of Chil3 (YM1) from primary cultures of brain microglia exposed to high levels of ATP. Sustained stimulation can reduce lysosomal function in microglia by increasing lysosomal pH and slowing autophagosome-lysosome fusion. P2X7 receptor stimulation can also cause lysosomal leakage, and the subsequent rise in cytoplasmic cathepsin B activates the NLRP3 inflammasome leading to caspase-1 cleavage and IL-1β maturation and release. Support for P2X7 receptor activation of the inflammasome following lysosomal leakage comes from data on primary microglia showing IL-1β release following receptor stimulation is inhibited by cathepsin B blocker CA-074. This pathway bridges endolysosomal and inflammatory roles and may provide a key mechanism for the increased inflammation found in age-dependent neurodegenerations characterized by excessive lysosomal accumulations. Regardless of whether the inflammasome is activated via this lysosomal leakage or the better-known K+-efflux pathway, the inflammatory impact of P2X7 receptor stimulation is balanced between the autophagic reduction of inflammasome components and their increase following P2X7-mediated priming. In summary, the P2X7 receptor modulates clearance of extracellular debris by microglial cells and mediates lysosomal damage that can activate the NLRP3 inflammasome. A better understanding of how the P2X7 receptor alters phagocytosis, lysosomal health, inflammation, and autophagy can lead to therapies that balance the inflammatory and clearance roles of microglial cells.

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Section: Discussionmentioning

confidence: 99%

The P2X7 Receptor in Microglial Cells Modulates the Endolysosomal Axis, Autophagy, and Phagocytosis

Campagno

Mitchell

2021

Front. Cell. Neurosci.

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“…M2 macrophages could antagonize and inhibit the inflammation caused by inflammatory molecules related to M1 macrophages [10][11][12]. Previous studies have reported that M2 microglia can promote recovery of motor function after spinal cord injury in mice and delay the progression of EAE [13,14]. Macrophages are homologous to microglia and are easier to obtain and culture.…”

Section: Introductionmentioning

confidence: 99%

Adoptive transfer of immunomodulatory M2 macrophages suppresses experimental autoimmune encephalomyelitis in C57BL/6 mice via blockading NF-κB pathway

Chu

Shi

Lang

et al. 2021

Clinical and Experimental Immunology

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Macrophages play important roles in multiple sclerosis (MS) and experimental autoimmune encephalomyelitis (EAE), and M2 macrophage may have anti-inflammatory effects. In this study, we elucidated the roles of M1 and M2 macrophages in the pathogenesis of EAE and the effects of treatment with M2 macrophages that target certain proinflammatory cytokines and with immunomodulatory preparations that beneficially influence the disease course. We found macrophages increased at the onset of clinical signs in the EAE group, consistent with an increased proportion of M1 macrophages and low numbers of M2 macrophages. As the disease progressed and the symptoms worsened, M1 macrophages decreased and M2 macrophages gradually increased until the peak. In the recovery stage, M2 macrophages gradually decreased. Treatment with M2 macrophages inhibited the nuclear factor kappa B (NF-κB) pathway, alleviated the symptoms of EAE, reduced inflammatory cell infiltration and demyelination in the central nervous system and decreased the numbers of macrophages in the spleens. BAY-11-7082, an NF-κB blocking agent, could reduce the total number of macrophages both in vivo and in vitro, effectively prevented EAE development and significantly inhibited EAE symptoms in mice. Our study demonstrates that macrophages may play a crucial role in the pathogenesis of EAE, while M2 macrophages have anti-inflammatory effects. Transfer of M2 macrophages to EAE mice can block the NF-κB pathway successfully and relieve EAE symptoms. Application of NF-κB blockers is useful in the prevention and treatment of EAE.

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“…This might be attributed to the increase in adenosine during conditions of increased metabolic demand or pathological states such as ischemia, pain and inflammation [ 49 ]. When necessary, ATP is increased and induces the A3R accumulation at the leading edge of immunocytes [ 50 ]. The increase in A3R and adenosine may be considered as an endogenous protective mechanism.…”

Section: Discussionmentioning

confidence: 99%

Activation of adenosine A3 receptor reduces early brain injury by alleviating neuroinflammation after subarachnoid hemorrhage in elderly rats

Deng

Wang

et al. 2020

Aging

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The incidence of subarachnoid hemorrhage (SAH) and hazard ratio of death increase with age. Overactivation of microglia contributes to brain damage. This study aimed to investigate the effects of A3 adenosine receptors (A3R) activation on neurofunction and microglial phenotype polarization in the context of SAH in aged rats. The A3R agonist (CI-IB-MECA) and antagonist (MRS1523) were used in the SAH model. Microglia were cultured to mimic SAH in the presence or absence of CI-IB-MECA and/or siRNA for A3R. The neurofunction and status of the microglial phenotype were evaluated. The P38 inhibitor SB202190 and the STAT6 inhibitor AS1517499 were used to explore the signaling pathway. The results showed that SAH induced microglia to polarize to the M(LPS) phenotype both in vivo and in vitro . CI-IB-MECA distinctly skewed microglia towards the M(IL-4) phenotype and ameliorated neurological dysfunction, along with the downregulation of inflammatory cytokines. Knockdown of A3R or inhibition of P38 and/or STAT6 weakened the effects of CI-IB-MECA on microglial phenotypic shifting. Collectively, our findings suggest that activation of A3R exerted anti-inflammatory and neuroprotective effects by regulating microglial phenotype polarization through P38/STAT6 pathway and indicated that A3R agonists may be a promising therapeutic options for the treatment of brain injury after SAH.

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Transplantation of M2-Deviated Microglia Promotes Recovery of Motor Function after Spinal Cord Injury in Mice

Cited by 136 publications

References 69 publications

The P2X7 Receptor in Microglial Cells Modulates the Endolysosomal Axis, Autophagy, and Phagocytosis

The P2X7 Receptor in Microglial Cells Modulates the Endolysosomal Axis, Autophagy, and Phagocytosis

Adoptive transfer of immunomodulatory M2 macrophages suppresses experimental autoimmune encephalomyelitis in C57BL/6 mice via blockading NF-κB pathway

Activation of adenosine A3 receptor reduces early brain injury by alleviating neuroinflammation after subarachnoid hemorrhage in elderly rats

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