The role of lipocalin 2 in the context of multiple sclerosis

Gasterich, Natalie; Ludwig, Andreas (Thesis advisor); Clarner, Tim (Thesis advisor); Zimmer-Bensch, Geraldine Marion (Thesis advisor)

Aachen : RWTH Aachen University (2021)
Dissertation / PhD Thesis

Dissertation, RWTH Aachen University, 2021


Multiple sclerosis (MS) is a chronic immune-mediated, demyelinating disease of the central nervous system (CNS). The histopathological hallmarks include the development of inflammatory lesions due to infiltrating immune cells and demyelinating plaques with severe loss of oligodendrocytes. The Cup/EAE mouse model is a suitable model to represent the main histopathological characteristics of MS. In this study, the role of Lipocalin 2 (LCN2) was investigated in the context of MS lesion development. First, LCN2 expression in the close vicinity of human MS lesions was investigated. Then, to get a deeper insight into the role of LCN2 in lesion formation, the Cup/EAE model was used and combined with a Lcn2 knockout phenotype, followed by histochemical analysis of the myelin status, immune cell infiltration and glial cell response. Focusing on astrocytes as the cellular source of LCN2 in the inflammatory brain, the basic function and chemokine expression of astrocytes were analyzed in complementary in vitro studies. Human MS lesions showed LCN2 expression at the border of active inflammatory lesions and LCN2+ immune cells were found surrounding capillary blood vessels. Comparing Lcn2 knockout mice with wild type mice in the Cup/EAE model, Lcn2 deficiency resulted in an increased inflammation characterized by higher numbers of Iba1+ microglia/monocytes and infiltrating T cells. In addition, Lcn2-deficient animals showed significantly increased myelin loss. This effect resulted from decreased myelin levels but not from elevated oligodendrocyte loss. In in vitro studies with primary astrocytes showed inducible LCN2 expression in response to inflammatory stimulation. Basic astrocytic functions like migratory behavior and morphological changes did not differ between wild type and Lcn2-deficient cells. Beyond, LCN2 expression was not a prerequisite for astrocytic chemokine expression in response to an inflammatory stimulus. The increased severity of histopathological hallmarks in Lcn2-deficient animals suggests a protective function of LCN2 with regard to myelin loss and the invasion of immune cells into the CNS, thus suggesting effects on the level of the blood brain barrier (BBB). Astrocytes themselves are a relevant source of LCN2 in the brain and do not need endogenous LCN2 to exhibit basic inflammatory responses. Further, astrocyte-derived LCN2 might target and influence neighboring cell populations such as other astrocytes, microglia and endothelial cells. In conclusion, I provide evidence that LCN2 is an important regulator of lesion formation in the context of MS. Further studies will focus on the underlying mechanisms of astrocyte-derived LCN2 as a modulator of the BBB.