Microglia in the juvenile brain after cranial irradiation

Radiotherapy is used to treat pediatric brain tumors and is often accompanied with debilitating late effects, such as cognitive decline. However, the mechanisms are poorly understood, and consequently there is still no effective treatment. The inflammatory response and microglia activation could change the micro-environment and effect neurogenesis resulting in impairment, and this seems to be one important factor eventually leading to cognitive decline.

Lithium has been used clinically many years for bipolar disorder, recent studies revealed neuroprotective effects of lithium. In the current thesis we show that lithium normalized irradiation induced neural precursor cell death, neurogenesis impairment, inflammation and cognitive decline without obvious side effects. Further studies demonstrated transient microglial activation and long-term microglia loss after irradiation. To further characterize the microglial response after irradiation, our bulk and single cell RNA sequencing data revealed that microglial activation returned towards normal levels 1 week after irradiation, indicating that microglia activation alone did not sustain the chronic inflammation after irradiation in the juvenile hippocampus. So therapeutic interventions aimed at targeting the chronic, detrimental inflammation after cranial radiotherapy may be required prior to or during radiotherapy in a clinical setting. Microglia are involved in almost all CNS diseases either directly or indirectly. Microglial depletion and repopulation have shown beneficial effects in many animal disease models; however, the signals regulating the microglia repopulation are poorly understood. Here we demonstrate that CX3CR1 could regulate residential microglia repopulation and their competition with peripheral infiltrating monocytes. Hence, CX3CR1-CX3CL1 axis could be manipulated for modulation of repopulation after microglial depletion.

In summary, our studies firstly demonstrate that lithium is a promising novel treatment for radiotherapy-induced intellectual impairment, secondly that there is a narrow time window for microglial therapeutic interventions after radiotherapy, and finally that CX3CR1 is crucial in the regulation of microglial repopulation after depletion. The knowledge generated in this thesis provides the foundation for further research, including clinical trial.

List of scientific papers

I. Kai Zhou, Cuicui Xie, Malin Wickström, Amalia Dolga, Yaodong Zhang, Tao Li, Yiran Xu, Carsten Culmsee, Changlian Zhu#, Klas Blomgren#. Lithium protects hippocampal progenitors, cognitive performance and hypothalamus-pituitary function after irradiation to the juvenile rat brain. Oncotarget. 2017, 8(21), 34111-34127. #Shared senior authorship.
https://doi.org/10.18632/oncotarget.16292

II. Wei Han, Takashi Umekawa, Kai Zhou, Xing-Mei Zhang, Makiko Ohshima, Cecilia A Dominguez, Robert Harris, Changlian Zhu#, Klas Blomgren#. Cranial irradiation induces transient microglia accumulation, followed by long-lasting inflammation and loss of microglia. Oncotarget. 2016, 7(50), 82305-82323. #Shared senior authorship.
https://doi.org/10.18632/oncotarget.12929

III. Ahmed M Osman, Ying Sun, Terry C Burns, Liqun He, Nigel Kee, Nuria Oliva-Vilarnau, Androniki Alevyzaki, Kai Zhou, Lauri Louhivuori, Per Uhlén, Eva Hedlund, Christer Betsholtz, Volker M. Lauschke, Julianna Kele, and Klas Blomgren. Radiation triggers a dynamic sequence of transient microglial alterations in juvenile brain. [Submitted]

IV. Kai Zhou, Jinming Han, Harald Lund, Shinobu Goto, Volker Lauschke, Nageswara Rao Boggavarapu, Ahmed Osman, Yuyu Wang, Dong liang, Cuicui Xie, Asuka Tachi, Ying Sun, Wei Han, Kristina Gemzell-Danielsson, Christer Betsholtz, Xing-Mei Zhang, Changlian Zhu, Bertrand Joseph, Robert Harris, Klas Blomgren. Repopulation of the microglial niche after genetic depletion is regulated by CX3CL1-CX3CR1 signaling. [Manuscript]