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. 2022 Jan 27;12(2):222.
doi: 10.3390/biom12020222.

Neuroinflammation Is Associated with GFAP and sTREM2 Levels in Multiple Sclerosis

Federica Azzolini  1 , Luana Gilio  1 , Luigi Pavone  1 , Ennio Iezzi  1 , Ettore Dolcetti  1 , Antonio Bruno  1 , Fabio Buttari  1 , Alessandra Musella  2   3 , Georgia Mandolesi  2   3 , Livia Guadalupi  2   3 , Roberto Furlan  4 , Annamaria Finardi  4 , Teresa Micillo  5 , Fortunata Carbone  5   6 , Giuseppe Matarese  6   7 , Diego Centonze  1   8 , Mario Stampanoni Bassi  1
Affiliations

Neuroinflammation Is Associated with GFAP and sTREM2 Levels in Multiple Sclerosis

Federica Azzolini et al. Biomolecules. .

Abstract

Background: Astrocytes and microglia play an important role in the inflammatory process of multiple sclerosis (MS). We investigated the associations between the cerebrospinal fluid (CSF) levels of glial fibrillary acid protein (GFAP) and soluble triggering receptors expressed on myeloid cells-2 (sTREM-2), inflammatory molecules, and clinical characteristics in a group of patients with relapsing-remitting MS (RRMS). Methods: Fifty-one RRMS patients participated in the study. Clinical evaluation and CSF collection were performed at the time of diagnosis. The CSF levels of GFAP, sTREM-2, and of a large set of inflammatory and anti-inflammatory molecules were determined. MRI structural measures (cortical thickness, T2 lesion load, cerebellar volume) were examined. Results: The CSF levels of GFAP and sTREM-2 showed significant correlations with inflammatory cytokines IL-8, G-CSF, and IL-5. Both GFAP and sTREM-2 CSF levels positively correlated with age at diagnosis. GFAP was also higher in male MS patients, and was associated with an increased risk of MS progression, as evidenced by higher BREMS at the onset. Finally, a negative association was found between GFAP CSF levels and cerebellar volume in RRMS at diagnosis. Conclusions: GFAP and sTREM-2 represent suitable biomarkers of central inflammation in MS. Our results suggest that enhanced CSF expression of GFAP may characterize patients with a higher risk of progression.

Keywords: astroglia; cerebrospinal fluid (CSF) biomarkers; cytokines; glial fibrillary acid protein (GFAP); microglia; multiple sclerosis (MS); neurodegeneration; neuroinflammation; soluble triggering receptor expressed on myeloid cells-2 (sTREM-2).

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Conflict of interest statement

The authors declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: F.B. acted as Advisory Board members of Teva and Roche and received honoraria for speaking or consultation fees from Merck Serono, Teva, Biogen Idec, Sanofi, and Novartis and non-financial support from Merck Serono, Teva, Biogen Idec, and Sanofi. RF received honoraria for serving on scientific advisory boards or as a speaker from Biogen, Novartis, Roche, and Merck and funding for research from Merck. DC is an Advisory Board member of Almirall, Bayer Schering, Biogen, GW Pharmaceuticals, Merck Serono, Novartis, Roche, Sanofi-Genzyme, and Teva and received honoraria for speaking or consultation fees from Almirall, Bayer Schering, Biogen, GW Pharmaceuticals, Merck Serono, Novartis, Roche, Sanofi-Genzyme, and Teva. He is also the principal investigator in clinical trials for Bayer Schering, Biogen, Merck Serono, Mitsubishi, Novartis, Roche, Sanofi-Genzyme, and Teva. His preclinical and clinical research was supported by grants from Bayer Schering, Biogen Idec, Celgene, Merck Serono, Novartis, Roche, Sanofi-Genzyme, and Teva. G.M. (Giuseppe Matarese) reports receiving research grant support from Merck, Biogen, and Novartis and advisory board fees from Merck, Biogen, Novartis, and Roche. The funders had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript, or in the decision to publish the results. F.A., M.S.B., A.B., A.M., E.D., E.I., F.C., L.G. (Luana Gilio), L.P., L.G. (Livia Guadalupi), A.F., G.M. (Georgia Mandolesi), and T.M.: nothing to report.

Figures

Figure 1
Figure 1
Correlation between CSF levels of GFAP, TREM-2 and inflammatory cytokines. Spearman’s correlations between CSF levels of GFAP and cytokines (A), sTREM2 and cytokines (B) and GFAP and sTREM2 (C). p-value is shown according to Benjamini-Hochberg (B-H) correction. Median concentration (min-max), pg/mL, of IL-5: 1,74(0–12,85); IL-8: 21.23(6.38–53.60); GCS-F: 15.59 (0–122.70); INF-γ: 2.45 (0–9.66); IL-9: 2.20 (0–50.33), GFAP: 65.78 (22.72–141.44); sTREM-2: 1858.25 (767.08–3839.92). Abbreviations: Cerebrospinal fluid (CSF); glial fibrillary acidic protein (GFAP); soluble triggering receptor expressed on myeloid cells-2 (sTREM2); interleukin (IL); granulocyte colony stimulating factor (G-CSF); interferon gamma (INFγ); Spearman’s rho (r); B-H p-value (p).
Figure 2
Figure 2
Correlation of CSF levels of GFAP and sTREM2 with clinical characteristics. Spearman’s correlations between CSF GFAP and sTREM2 and age at lumbar puncture (A,B) and BREMSO (E,F). Comparison between CSF GFAP or sTREM2 levels in male and female patients (C,D), Mann–Whitney U-test. Abbreviations: Cerebrospinal fluid (CSF); glial fibrillary acidic protein (GFAP); soluble triggering receptor expressed on myeloid cells-2 (sTREM2); Lumbar puncture (LP); male (M); female (F); Bayesian Risk Estimate for Multiple Sclerosis at Onset (BREMSO); Spearman’s rho (r); p-value (p)
Figure 3
Figure 3
Correlations between CSF GFAP and sTREM2 and MRI structural measures. Spearman’s correlations between CSF GFAP and MRI structural measures (A) and sTREM2 and MRI measures (B). Abbreviations: Cerebrospinal fluid (CSF); glial fibrillary acidic protein (GFAP); soluble triggering receptor expressed on myeloid cells-2 (sTREM2); Spearman’s rho (r); p-value (p).
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