Cytokine and Complement Response in the Glaucomatous βB1-CTGF Mouse Model

• Published in: Frontiers in cellular neuroscience Vol. 15; p. 718087
• Main Authors: Reinehr, Sabrina, Doerner, Johanna D., Mueller-Buehl, Ana M., Koch, Dennis, Fuchshofer, Rudolf, Dick, H. Burkhard, Joachim, Stephanie C.
• Format: Journal Article
• Language: English
• Published: Lausanne Frontiers Research Foundation 18-11-2021; Frontiers Media S.A
• Subjects: Anaphylatoxins; Antibodies; Apoptosis; Axons; Cell death; Chemokines; Classical pathway; Complement activation; Complement component C1q; Complement component C3; Complement component C5a; complement system; Connective tissue growth factor; CXCL1; CXCL10 protein; Cytokines; Gene expression; Glaucoma; Membrane attack complex; Neurodegenerative diseases; Neuroscience; Optic nerve; Retinal ganglion cells; Risk factors; Software; Transgenic animals; Transgenic mice; βB1-CTGF; γ-Interferon; United States > US; Germany
• ISSN: 1662-5102; 1662-5102
• DOI: 10.3389/fncel.2021.718087

Glaucoma is a complex neurodegenerative disease leading to a loss of retinal ganglion cells (RGCs) and optic nerve axons. An activation of the complement system seems to contribute to cell loss in this disease. Hence, we investigated a possible initiation of the complement system and the cytokine response in the βB1-CTGF glaucoma model. In these mice, intraocular pressure is elevated, which is the main glaucoma risk factor in patients, and RGC loss occurs at 15 weeks of age. Therefore, quantitative real-time PCR and immunohistological experiments were performed in 5-, 10-, and 15-week-old βB1-CTGF animals and their corresponding wildtypes (WT) to analyze the expression of several complement system factors. We could show that mRNA levels of the terminal complement pathway components
C3
and C5 (
Hc
) were upregulated at 10 weeks. In accordance, more C3
+
and membrane attack complex
+
cells were observed in transgenic retinae. Further, the C5a receptor anaphylatoxin receptor (
C5ar
) and the complement component C5a receptor 1 (
C5ar1
; CD88) mRNA levels were upregulated in 10- and 15-week-old βB1-CTGF mice. Interestingly, all three activation routes of the complement system were elevated in βB1-CTGF mice at some age. Especially C1q, as a marker of the classical pathway, was significantly increased at all investigated ages. Furthermore, mRNA expression levels of interferon-γ (
Infg
) were upregulated at 5 weeks, while
Cxcl1
and
Cxcl2
mRNA levels were upregulated at 10 and 15 weeks. The mRNA levels of the chemokines
Cxcl10
were increased at all ages in βB1-CTGF mice. These results lead to the assumption that in these transgenic mice, a complement activation mainly through the classical pathway as well as a cytokine response plays a major role in cell death.