Transient microglial and prolonged astroglial upregulation of osteopontin following transient forebrain ischemia in rats

Choi, Jeong-Sun; Kim, Ha-Young; Cha, Jung-Ho; Choi, Jun-Sub; Lee, Mun‐Yong

doi:10.1016/j.brainres.2007.03.016

Cited by 43 publications

(51 citation statements)

References 23 publications

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“…In accordance with previous studies including our own (Choi et al, 2007;Ellison et al, 1998;Lee et al, 1999;Wang et al, 1998;Yan et al, 2009), OPN mRNA was induced in a subpopulation of Iba1-immunoreactive cells in the ischemic core. These were large and ameboid-like in shape and were colabeled with ED1, the lysosomal marker, indicating that they were phagocytic macrophages.…”

Section: Discussionsupporting

confidence: 91%

“…Antisense and sense riboprobes labeled with digoxigenin (DIG) and specific for OPN were prepared using RT/ PCR and in vitro transcription, as described in detail previously (Choi et al, 2007). Coronal cryostat sections (25-lm thick) were hybridized with antisense or sense probes diluted in hybridization solution (150 ng mL 21 ) at 52°C for 18 h. Hybridization was visualized using an alkaline phosphatase-conjugated sheep anti-DIG antibody (Roche, Germany; dilution 1:2,000) with 4-nitroblue tetrazolium chloride (0.35 mg mL…”

Section: In Situ Hybridization Histochemistry and Double/triple Labelingmentioning

confidence: 99%

“…Several studies have been performed on the ischemic brain where OPN induction is evident in microglia/macrophages (Choi et al, 2007;Ellison et al, 1998Ellison et al, , 1999Lee et al, 1999;Schroeter et al, 2006;Wang et al, 1998;Yan et al, 2009) and reactive astrocytes (Choi et al, 2007), suggesting that OPN acts as a chemoattractant that recruits microglia, macrophage and astrocytes to assist in the formation of a glial scar following ischemic injury. In addition, it has been reported that OPN reduced ischemic cell death in models of ischemic injury in vitro and in vivo, with the neuroprotective effects of OPN being mediated via the activation of Akt and p42/44 mitogen-activated protein kinases (Meller et al, 2005).…”

Section: Introductionmentioning

confidence: 99%

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Osteopontin: Correlation with phagocytosis by brain macrophages in a rat model of stroke

Shin

Kim

Choi

et al. 2010

Glia

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Osteopontin (OPN) is an adhesive glycoprotein linked to a variety of pathophysiological processes. We investigated whether OPN might act as an opsonin in the diseased brain by studying the postischemic expression and localization of OPN mRNA and protein in a rat model of ischemic stroke. In addition, we characterized the subcellular localization of OPN protein in the ischemic brain core. Induction of OPN mRNA occurred in activated microglia/macrophages in the ischemic core on days 3-7 after reperfusion and this was sustained up to day 28, at least. OPN protein was synthesized and secreted by brain macrophages, which first surrounded damaged striatal white matter tracts and then infiltrated into them. Punctate OPN-immunoreactive profiles were scattered throughout the infarction core except in white matter bundles. Electron microscopy showed the localization of OPN protein along the membranes lining what appeared to be the debris of dead neurons. These were located in the extracellular space and within the cytoplasm of brain macrophages, indicating that the OPN protein accumulated selectively on the surface of dead cells, most of which were phagocytosed subsequently by brain macrophages. However, no significant induction of OPN occurred in degenerating striatal white matter tracts or in brain macrophage-engulfed axonic or myelin debris. These data suggest that OPN secreted by brain macrophages in this rat model of stroke might be involved in the phagocytosis of fragmented cell debris and possibly not in the phagocytosis of axonic or myelin debris.

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Section: Discussionsupporting

confidence: 91%

Section: In Situ Hybridization Histochemistry and Double/triple Labelingmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Osteopontin: Correlation with phagocytosis by brain macrophages in a rat model of stroke

Shin

Kim

Choi

et al. 2010

Glia

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“…In addition, astrocytes participate in the accumulation and structural expansion of calcium deposits in excitotoxic lesions (Oliveira et al 2003), and heterogeneity of the astroglial population is a contributing factor to variations in regional vulnerability to neurodegeneration and calcium deposition (Rodríguez et al 2004). In this context, it is of interest that astroglial OPN expression in the hippocampus is first induced at 10 days after ischemia (Choi et al 2007), further increased at 4 weeks, and maintained at elevated levels for at least 8 weeks. These observations, together with our new findings, suggest that astrocytes express OPN in the early phase of calcium deposition in the ischemic hippocampus and thus astroglial OPN is centrally involved in calcium precipitation in the ischemic brain.…”

Section: Discussionmentioning

confidence: 99%

“…Taken together, these data suggest that OPN participates in the regulation of ectopic calcification in the ischemic brain. In this regard, it is interesting to note that in addition to being expressed in activated microglia/macrophages within the first few days after transient forebrain ischemia, OPN protein accumulated in the CA1 hippocampal region over a 4-week period following the insult (Choi et al 2007). Thus, long-lasting and progressive OPN accumulation in the ischemic hippocampus may be associated with calcium deposits, although the precise nature of these OPN deposits is still unknown.…”

mentioning

confidence: 99%

Sustained Expression of Osteopontin Is Closely Associated with Calcium Deposits in the Rat Hippocampus After Transient Forebrain Ischemia

Park

Shin

Kim

et al. 2012

J Histochem Cytochem.

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The present study was designed to evaluate the extent and topography of osteopontin (OPN) protein expression in the rat hippocampus 4 to 12 weeks following transient forebrain ischemia, and to compare OPN expression patterns with those of calcium deposits and astroglial and microglial reactions. Two patterns of OPN staining were recognized by light microscopy: 1) a diffuse pattern of tiny granular deposits throughout the CA1 region at 4 weeks after ischemia and 2) non-diffuse ovoid to round deposits, which formed conglomerates in the CA1 pyramidal cell layer over the chronic interval of 8 to 12 weeks. Immunogold-silver electron microscopy and electron probe microanalysis demonstrated that OPN deposits were indeed diverse types of calcium deposits, which were clearly delineated by profuse silver grains indicative of OPN expression. Intracellular OPN deposits were frequently observed within reactive astrocytes and neurons 4 weeks after ischemia but rarely at later times. By contrast, extracellular OPN deposits progressively increased in size and appeared to be gradually phagocytized by microglia or brain macrophages and some astrocytes over 8 to 12 weeks. These data indicate an interaction between OPN and calcium in the hippocampus in the chronic period after ischemia, suggesting that OPN binding to calcium deposits may be involved in scavenging mechanisms.

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Effects of astrocyte‐targeted production of interleukin‐6 in the mouse on the host response to nerve injury

Almolda

Villacampa

Manders

et al. 2014

Glia

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Interleukin-6 (IL-6) is a pleiotropic cytokine with a key role in the control of inflammatory/immune responses. In the central nervous system (CNS), an increase in IL-6 occurs in a wide range of pathological conditions such as excitotoxicity and traumatic brain injury. We evaluated the effects of astrocyte-targeted production of IL-6 in the CNS in the sterile-nerve injury model of facial nerve axotomy. To accomplish this, facial nerve transection was performed in transgenic mice (glial fibrillary acidic protein [GFAP]-IL6Tg) with IL-6 production under the GFAP promoter. Neuronal death, glial activation, lymphocyte recruitment, and integrin expression were evaluated by immunohistochemistry and flow cytometry from 3 to 28 days postinjury. Our findings revealed an increase in motor neuron cell death in GFAP-IL6Tg mice correlating with changes in the microglial activation pattern, characterized principally by less attachment to neurons and reduced expression of both CD11b and CD18. We also found a higher CD4(+) T-lymphocyte recruitment in GFAP-IL6Tg mice. In addition, changes in the expression pattern of different integrins and their receptors were observed in transgenic animals. Specifically, alterations in osteopontin expression in motor neurons and its receptors CD44 and CD49e in lymphocytes and microglia, respectively, which may account for the variations related to glial reactivity and lymphocyte infiltration. In conclusion, our results indicated that forced local production of IL-6 has a direct impact on the outcome of nerve injury in the CNS inducing an increase in neurodegeneration, changes in glial response, and lymphocyte recruitment as well as in the expression of different integrins and their receptors.

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Transient microglial and prolonged astroglial upregulation of osteopontin following transient forebrain ischemia in rats

Cited by 43 publications

References 23 publications

Osteopontin: Correlation with phagocytosis by brain macrophages in a rat model of stroke

Osteopontin: Correlation with phagocytosis by brain macrophages in a rat model of stroke

Sustained Expression of Osteopontin Is Closely Associated with Calcium Deposits in the Rat Hippocampus After Transient Forebrain Ischemia

Effects of astrocyte‐targeted production of interleukin‐6 in the mouse on the host response to nerve injury

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