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. 2018 Nov 9;13(11):e0206597.
doi: 10.1371/journal.pone.0206597. eCollection 2018.

Fetuin-A protein distribution in mature inflamed and ischemic brain tissue

Miriam Christina Heinen  1   2   3 , Anne Babler  2 , Joachim Weis  3   4 , Johannes Elsas  1   2 , Kay Nolte  3 , Markus Kipp  5 , Willi Jahnen-Dechent  2 , Martin Häusler  1
Affiliations

Fetuin-A protein distribution in mature inflamed and ischemic brain tissue

Miriam Christina Heinen et al. PLoS One. .

Abstract

Background: The liver-derived plasma protein fetuin-A is strongly expressed during fetal life, hence its name. Fetuin-A protein is normally present in most fetal organs and tissues, including brain tissue. Fetuin-A was neuroprotective in animal models of cerebral ischemia and lethal chronic inflammation, suggesting a role beyond the neonatal period. Little is known, however, on the presence of fetuin-A in mature human brain tissue under different physiological and pathological conditions.

Methods: We studied by immunohistochemistry (IHC) the distribution of fetuin-A protein in mature human brain autopsy tissues from patients without neurological disease, patients with inflammatory brain disorders, and patients with ischemic brain lesions. To identify fetuin-A-positive cells in these tissues we co-localized fetuin-A with GFAP (astrocytes) and CD68 (macrophages, activated microglia).

Results and discussion: Unlike previous reports, we detected fetuin-A protein also in mature human brain as would be expected from an abundant plasma protein also present in cerebrospinal fluid. Fetuin-A immunoreactivity was increased in ischemic white matter and decreased in inflamed cerebellar tissue. Fetuin-A immunostaining was predominantly associated with neurons and astrocytes. Unlike the developing brain, the adult brain lacked fetuin-A immunostaining in CD68-positive microglia. Our findings suggest a role for fetuin-A in tissue remodeling of neonatal brain, which becomes obsolete in the adult brain, but is re-activated in damaged brain tissue. To further assess the role of fetuin-A in the mature brain, animal models involving ischemia and inflammation need to be studied.

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Conflict of interest statement

The authors have declared that no competing interests exist.

Figures

Fig 1
Fig 1. Typical views of fetuin-A immunostaining in the choroid plexus, the dentate gyrus, the cornu ammonis and the cortex.
(A) Strong fetuin-A immunostaining (red color) in the choroid plexus, which transports and secretes fetuin-A into the cerebrospinal fluid. (B) Cell-associated fetuin-A immunostaining in the dentate gyrus, (C) the cornu ammonis, and (D) in the cortex.
Fig 2
Fig 2. Fetuin-A expression in controls.
(Displayed are mean ± SE, individual scores for each case indicated by dots). In the cortex and adjacent white matter fetuin-A-positive cells were equally distributed in cortical and white matter structures. In basal ganglia fetuin-A positive cells were diffusively scattered over all regions. In temporal lobes fetuin-A positive cells were found in choroid plexus, periventricular zones, ependyma, pallium and hippocampus, with highest values in the choroid plexus and ependyma cells. In the cerebellum Purkinje cells were found to strongly express fetuin-A.
Fig 3
Fig 3. Fetuin-A expression of score 3 areas in cortex and adjacent white matter.
Strong focal staining was significantly more frequent in ischemic lesions compared to controls mainly due to focal staining in the white matter of ischemic brains. Inflammatory tissue, in contrast, did not show altered immunoreactivity compared to control brain tissue. Cerebral tissues of 20 inflammatory cases, 8 ischemic cases and 13 control cases were evaluated. * p < 0.05.
Fig 4
Fig 4. Fetuin-A expression in the temporal lobe of inflammatory cases (n = 16) and controls (n = 14).
(Displayed are mean ± SE, individual scores for each case). Compared to controls tissue samples from patients with inflammatory diseases tended to show lower staining scores although the difference was not significant.
Fig 5
Fig 5. Percentage of score 3 areas in the temporal lobes.
In both groups, strongest fetuin-A staining was detected in the choroid plexus cells. Focal accumulations (“score 3” areas) were also frequent in ependyma cells and along the periventricular zones. We further detected focal accumulations of fetuin-A positive cells in temporal cortex, the adjacent white matter and hippocampus of some cases. Within each subregion Fisher´s exact test did not show significant differences between the control and inflammation groups. Between subregions however, there were statistically significant differences in score 3 areas in that e.g. choroid plexus showed 40–57% score 3 staining intensity and white matter showed less than 10% score 3 staining intensity.
Fig 6
Fig 6. Immunoreactivity of Purkinje cells in inflammatory and control cases.
(A) Fetuin-A staining (pink) of Purkinje cells (arrows) in non-inflamed brain tissue. (B) Purkinje cells in brain tissue of a patient with meningitis showed no fetuin-A immunoreactivity.
Fig 7
Fig 7. Fetuin-A expression in the cerebellum of inflammatory cases (n = 17) and controls (n = 14).
(Displayed are mean ± SE individual scores for each case.) Fetuin-A immunoreactivity was generally decreased in inflammation, reaching statistical significance in the case of Purkinje cells (**p = 0.001). Fetuin-A immunoreactivity also tended to be lower in cerebellar white matter and granular cells, which however, did not reach statistical significance due to large variation.
Fig 8
Fig 8. Identification of cells by double immunostaining.
Co-localizations of fetuin-A (red) with GFAP (green) in the subpial area of a control case (A) and in the cortex of an inflammatory case (B). Activated microglia were detected in every tissue sample, including control cases. The presence of activated microglia was confirmed by positive CD68 staining and the typical amoeboid morphology of microglia (C). Fetuin-A-positive pyramidal neurons could be identified in their characteristic shape and localization (D). Counterstaining with DAPI (blue).
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This work was supported by the START program of the Medical faculty of RWTH Aachen University and by grants awarded to W-JD by the IZKF Aachen of the Medical Faculty or RWTH Aachen University, the German Research Foundation (DFG SFB/TRR219-Project C-03). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. All authors declare no conflict of interest.