Floßdorf, Juliane: The role of PPARγ in myeloid cells in experimental autoimmune encephalomyelitis. - Bonn, 2013. - Dissertation, Rheinische Friedrich-Wilhelms-Universität Bonn.
Online-Ausgabe in bonndoc: https://nbn-resolving.org/urn:nbn:de:hbz:5n-31971
urn: https://nbn-resolving.org/urn:nbn:de:hbz:5n-31971,
author = {{Juliane Floßdorf}},
title = {The role of PPARγ in myeloid cells in experimental autoimmune encephalomyelitis},
school = {Rheinische Friedrich-Wilhelms-Universität Bonn},
year = 2013,
month = may,

note = {Multiple sclerosis (MS) is a common chronic inflammatory demyelinating disease of the central nervous system (CNS) affecting more than 1 million people worldwide. It mainly affects young adults and has a great impact on the social economic situation. Although several therapeutic drugs are available for slowing down progression or reducing number of relapses there is a clear need for more efficacious therapies.
The peroxisome proliferator-activated receptor γ (PPARγ), a nuclear transcription factor with anti-inflammatory effects, influences pro-inflammatory responses of several immune cell types during experimental autoimmune encephalomyelitis (EAE), the animal model of MS, which ameliorates the disease course and reduces neuronal damage. Hence, PPARγ seems to be a promising target for therapeutic treatment during EAE and MS.
The aim of this thesis was to investigate the relevance of PPARγ specifically in myeloid cells for control of their inflammatory activity in vitro and in vivo. To this end, we made use of a conditional knock-out mouse model which exhibits targeted deletion of PPARγ in M-lysozyme (LysM)-expressing cells (LysM-PPARγKO mice) which comprise myeloid cells such as monocytes, macrophages, CNS-resident microglial cells as well as neutrophilic granulocytes.
We observed significantly enhanced production of pro-inflammatory cytokines, chemokines and neurotoxic mediators by PPARγ-deficient (PPARγKO) primary microglial cells and macrophages compared to PPARγWT cells in vitro. Importantly, we could demonstrate in vivo, that LysM-PPARγKO mice exhibited an aggravated course of disease during the effector phase of EAE. This aggravation was accompanied by a more pronounced local inflammatory milieu within the CNS as pro-inflammatory cytokines such as tumor necrosis factor (TNF) α, interleucin (IL) - 12 and IL-6 as well as chemokines like CCL2 and CCL5 were increasingly expressed in LysM-PPARγKO mice. Furthermore, this exacerbation was accompanied by an increase of CNS-invading macrophages and T cells as well as an increase in the activation status of PPARγKO myeloid cells, which show higher levels of Cluster of Differentiation (CD40) and major histocompatibility complexes (MHC) -II expression.
Furthermore, this thesis addressed the question which subgroup of myeloid cells is the main target for PPARγ-mediated regulation during EAE. By combining monocyte transfer and depletion experiments we identified the myeloid cell population that represents the main population regulated by PPARγ during EAE, i.e. Ly6Chi inflammatory monocytes. Transfer of PPARγ-deficient monocytes into EAE-diseased mice resulted in a more pronounced aggravation of disease than the transfer of wildtype monocytes. In line with this, depletion of inflammatory monocytes during EAE not only ameliorated the disease course of both, LysM-PPARγKO and LysMPPARγWT mice but also abrogated the differences observed during the effector phase in LysM-PPARγKO mice compared to their wildtype littermates.
In summary, these data provide evidence that PPARγ controls the activation status of myeloid cells during autoimmune responses, thereby affecting the extent of CNS inflammation and hence neuronal damage in EAE. Therefore PPARγ in myeloid cells represents a promising therapeutic target for future treatment of CNS-infammation in MS.},

url = {http://hdl.handle.net/20.500.11811/5677}

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