Microglia, macrophages, perivascular macrophages, and pericytes: a review of function and identification

Guillemin, Gilles J.; Brew, Bruce J.

doi:10.1189/jlb.0303114

Cited by 467 publications

(400 citation statements)

References 166 publications

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“…4A and data not shown). We confirmed the effectiveness of these treatments by measuring nitric oxide (NO) release [27][28][29]. As expected, IFN-g alone and IFN-g in combination with TNF-a or LPS induced, while both IL-4 and IL-13 blocked, NO release (Fig.…”

supporting

confidence: 81%

Dynamic regulation of the P2X₄ receptor in alveolar macrophages by phagocytosis and classical activation

Stokes

Surprenant

2009

Eur J Immunol

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ATP-gated P2X 4 receptors (P2X 4 R) in macrophages and microglia have been implicated in neuropathic and inflammatory pain by currently unidentified mechanisms. P2X 4 R are found predominantly in intracellular lysosomal compartments but can be rapidly trafficked to the surface membrane by procedures that induce endolysosomal secretion. We studied total and surface membrane P2X 4 R protein expression by Western blot and biotinylation assays and functional expression by whole-cell patch clamp assays in human and rat alveolar macrophages in response to phagocytosis of zymosan and opsonized zymosan bioparticles and to classical and alternative macrophage activation. Unstimulated macrophages showed high total protein expression but very low functional expression. Phagocytosis rapidly (within 4 h) increased functional P2X 4 R expression by 2-to 7-fold as did chloroquine, an agent known to induce lysosomal secretion. In contrast, classical activation of macrophage for 48 h with IFN-c and TNF-a or IFN-c and LPS reduced surface and functional P2X 4 R expression by 3-fold without altering total P2X 4 R protein levels. Alternative activation with IL-4 or IL-13 did not alter total, surface or functional expression of P2X 4 R. This is the first study of the regulation of P2X 4 R in macrophages by physiological stimuli and presents a picture whereby P2X 4 R become functional in response to initial phagocytic stimuli but return to a non-functional state during sustained activation by classical macrophage activation.Key words: Inflammation . Ion channels . Patch-clamp . Purine receptors Introduction Extracellular ATP acts as a ''danger signal'' when it is released from cells during tissue damage and inflammation; it acts on metabotropic (G-protein coupled) P2Y and ionotropic (cation channel) P2X purinergic receptors to affect several inflammatory and immune responses [1,2]. There are seven members of the P2X receptor family (P2X 1-7 R) that show widespread distribution in both neuronal and non-neuronal tissues [3]. Two of these seven members, P2X 4 R and P2X 7 R, have generated increasing interest as potential anti-inflammatory drug targets [2,4,5]. The case for P2X 7 R is now well established: Stimulation of P2X 7 R in activated monocytes, macrophages and microglia leads to rapid release of pro-inflammatory IL-1b and IL-18 cytokines, to phospholipase D activation and, if stimulation is sustained, to apopotosis [1,[3][4][5]. Classical activation of macrophages, generally induced by IFN-g and/or LPS, up-regulates P2X 7 R mRNA and protein levels and functional expression [6,7] and this correlates well with a role for P2X 7 R in bacterial killing [8,9]. Recently, highly selective and potent P2X 7 R antagonists have been identified [10] with one of these showing initial positive results in Phase II clinical trials for rheumatoid arthritis [11]. The case for P2X 4 R remains tentative, largely due to the absence of selective P2X 4 R antagonists and the complicating presence of P2X 7 R, which is generally co-expressed with P2X 4 R in ...

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supporting

confidence: 81%

Dynamic regulation of the P2X₄ receptor in alveolar macrophages by phagocytosis and classical activation

Stokes

Surprenant

2009

Eur J Immunol

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“…These divergent results might be partly because of the differences in the membranous and biochemical markers between peripheral macrophages and microglia, considering microglia is specified in the central nervous system (CNS) microenvironment. 35 Moreover, it is highly possible that in the Jmjd3 À / À BMMs, the compensentary mechanisms may interfere the H3K27me3-involved gene regulation. Interestingly, knockdown of Jmjd3 in the microglia even without any treatment compromised the expression of various M2 genes, suggesting that the mechanism of Jmjd3-regulated M2 polarization is very intrinsic and cell-autonomous.…”

Section: Discussionmentioning

confidence: 99%

Jmjd3 is essential for the epigenetic modulation of microglia phenotypes in the immune pathogenesis of Parkinson’s disease

et al. 2013

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Classical activation (M1 phenotype) and alternative activation (M2 phenotype) are the two polars of microglial activation states that can produce either detrimental or beneficial effects in the central nervous system (CNS). Harnessing the beneficial properties of microglia cells by modulating their polarization states provides great potential for the treatment of Parkinson's disease (PD). However, the epigenetic mechanism that regulates microglia polarization remains elusive. Here, we reported that histone H3K27me3 demethylase Jumonji domain containing 3 (Jmjd3) was essential for M2 microglia polarization. Suppression of Jmjd3 in N9 microglia inhibited M2 polarization and simultaneously exaggerated M1 microglial inflammatory responses, which led to extensive neuron death in vitro. We also observed that the suppression of Jmjd3 in the substantia nigra (SN) in vivo dramatically caused microglial overactivation and exacerbated dopamine (DA) neuron death in 1-methyl-4-phenyl-1, 2, 3, 6-tetrahydropyridine (MPTP)-intoxicated mouse model of PD. Moreover, we showed that the Jmjd3 level was lower in the midbrain of aged mice, which was accompanied by an elevated level of H3K27me3 and an increased ratio of M1 to M2 markers, suggesting that aging is an important factor in switching the microglia phenotypes. Overall, our studies indicate that Jmjd3 is able to enhance the polarization of M2 microglia by modifying histone H3K27me3, and therefore it has a pivotal role in the switch of microglia phenotypes that may contribute to the immune pathogenesis of PD.

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“…2 D). OX-42 is a cell adhesion protein found in both microglial cells and macrophages that is overexpressed on activation of either of these cell types (Guillemin and Brew, 2004). As microglial cells are not present within sensory ganglia (Olsson, 1990), the increased OX-42 mRNA levels observed in both TG and DRG probably reflected the recruitment and/or activation of macrophages.…”

Section: Sensory Gangliamentioning

confidence: 99%

Differential Implication of Proinflammatory Cytokine Interleukin-6 in the Development of Cephalic versus Extracephalic Neuropathic Pain in Rats

et al. 2008

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Responses resulting from injury to the trigeminal nerve exhibit differences compared with those caused by lesion of other peripheral nerves. With the aim of elucidating the physiopathological mechanisms underlying cephalic versus extracephalic neuropathic pain, we determined the time course expression of proinflammatory cytokines interleukin-6 (IL-6) and IL-1␤, neuronal injury (ATF3), macrophage/microglial (OX-42), and satellite cells/astrocyte (GFAP) markers in central and ganglion tissues in rats that underwent unilateral chronic constriction injury (CCI) to either infraorbital nerve (IoN) (cephalic area) or sciatic nerve (SN) (extracephalic area). Whereas CCI induced microglial activation in both models, we observed a concomitant upregulation of IL-6 and ATF3 in the ipsilateral dorsal horn of the lumbar cord in SN-CCI rats but not in the ipsilateral spinal nucleus of the trigeminal nerve (Sp5c) in IoN-CCI rats. Preemptive treatment with minocycline (daily administration of 20 mg/kg, i.p., for 2 weeks) partially prevented pain behavior and microglial activation in SN-CCI rats but was ineffective in IoN-CCI rats. We show that IL-6 can upregulate OX-42 and ATF3 expression in cultured microglia and neurons from spinal cord, respectively, as well as in the dorsal horn after acute intrathecal administration of the cytokine. We propose that IL-6 could be one of the promoters of the signaling cascade leading to abnormal pain behavior in SN-CCI but not IoN-CCI rats. Our data further support the idea that different pathophysiological mechanisms contribute to the development of cephalic versus extracephalic neuropathic pain.

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Microglia, macrophages, perivascular macrophages, and pericytes: a review of function and identification

Cited by 467 publications

References 166 publications

Dynamic regulation of the P2X₄ receptor in alveolar macrophages by phagocytosis and classical activation

Dynamic regulation of the P2X₄ receptor in alveolar macrophages by phagocytosis and classical activation

Jmjd3 is essential for the epigenetic modulation of microglia phenotypes in the immune pathogenesis of Parkinson’s disease

Differential Implication of Proinflammatory Cytokine Interleukin-6 in the Development of Cephalic versus Extracephalic Neuropathic Pain in Rats

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Microglia, macrophages, perivascular macrophages, and pericytes: a review of function and identification

Cited by 467 publications

References 166 publications

Dynamic regulation of the P2X4 receptor in alveolar macrophages by phagocytosis and classical activation

Dynamic regulation of the P2X4 receptor in alveolar macrophages by phagocytosis and classical activation

Jmjd3 is essential for the epigenetic modulation of microglia phenotypes in the immune pathogenesis of Parkinson’s disease

Differential Implication of Proinflammatory Cytokine Interleukin-6 in the Development of Cephalic versus Extracephalic Neuropathic Pain in Rats

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Dynamic regulation of the P2X₄ receptor in alveolar macrophages by phagocytosis and classical activation

Dynamic regulation of the P2X₄ receptor in alveolar macrophages by phagocytosis and classical activation