Constitutive heterogeneity and response diversity of microglia in pathological conditions

von Ulla Gertig
Dissertation
Datum der mündl. Prüfung:2016-12-12
Erschienen:2016-12-16
Betreuer:Prof. Dr. Wolfgang Brück
Gutachter:Prof. Dr. Wolfgang Brück
Gutachter:Prof. Dr. Dr. Hannelore Ehrenreich
Gutachter:Prof. Dr. Fred Wouters
Gutachter:Prof. Dr. Jutta Gärtner
Gutachter:Dr. Hauke Werner
Gutachter:Prof. Dr. Ralf Heinrich
Zum Verlinken/Zitieren: http://dx.doi.org/10.53846/goediss-6043

 

 

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Microglia, resident myeloid cells of the CNS, execute an enormous variety of different functions like tissue surveillance, nursing of synapses, phagocytosis of foreign material or debris, and initiation of appropriate immune responses upon CNS infection and damage (Hanisch and Kettenmann, 2007; Kettenmann et al., 2011). The duration of an immune response is thereby selflimiting as it resolves with a successful combat of the threat. A sustaining threat, however, can lead to an over-activation of microglia which switches their initially beneficial effect to a rather detrimental outcome. This disturbed microglia phenotype leads to a variety of neuropsychiatric disorders or neurodegenerative diseases and aggravates the disease outcomes, mostly resulting in neurotoxicity (Gold and Khoury, 2015; Hickman et al., 2008; von Bernhardi et al., 2015). Targeting microglia is therefore a promising therapeutic approach to oppose those diseases (Chen et al., 2014;Wes et al., 2016). Though,microglia functions are inmost cases performed by amere subpopulation, a drug targeting the whole microglia population would thereby effect not only the subsets causing the neurotoxicity but also the subsets which try to resolve the disease (Biber et al., 2016; Marshall et al., 2014; Olah et al., 2012; Venkatesan et al., 2010). Thus, to develop a useful drug, which specifically targets a harmful subpopulation of microglia, the microglial organization principle needs to be unraveled beforehand. This study focused on the functional heterogeneity of a microglial immune response by investigating cytokine producing microglia subsets confronted with a variety of stimuli conditions in different environmental contexts. I observed a highly specific adaptation of those subsets. The degree of adaptation is thereby dependent on the investigated function, the used stimulus, the stimulus intensity and the microglia density. Further analysis revealed that the subpopulations are not performing one single function butmultiple functions at once. Function specific subpopulations are thereby composed of subpopulations which perform other functions as well. These results demonstrate an almost infinite organization complexity ofmicroglia subsets, highlighting the importance of further research to fully understand the nature of microglia.
Keywords: Microglia; Hetereogeneity; in vitro
 
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