Repopulation of a microglia-depleted central nervous system : molecular characterization during homeostasis and disease
Author: Han, Jinming
Date: 2021-03-12
Location: CMM Lecture Hall, L8:00 024, Karolinska University Hospital, Solna
Time: 09.00
Department: Inst för klinisk neurovetenskap / Dept of Clinical Neuroscience
View/ Open:
Thesis (1018.Kb)
Abstract
Microglia are predominant tissue resident macrophages within the central nervous system (CNS), and contribute to both CNS development and homeostasis. During disease conditions microglia undergo transcriptional re-programming and their dysfunction is implicated in a multitude of disorders, such as multiple sclerosis (MS). How microglia could be therapeutically targeted is a current research focus. Recent experimental microglial depletion methods using conditional genetic targeting and pharmacological therapies have broadened our perspective of these multi-tasking microglia. Newly repopulated microglia following experimental microglial ablation hold great promise for reducing neuroinflammation and treating a variety of neurological disorders.
In Study 1 our results indicated that microglia could be ablated (approximately 95%) by systemic use of tamoxifen in Cx3cr1CreER/+Rosa26DTA/+ mice. Microglial repopulation ensued through both the proliferation of surviving microglia in the CNS, and from the infiltration of Ly6Chi monocytes. Under this condition infiltrating monocytes could be shaped into microglia-like cells by the CNS microenvironment. Furthermore, isolated newly repopulated resident microglia and infiltrating microglia-like cells following experimental depletion exhibited differential functionality in vitro, such as phagocytic capacity and cytokine production.
In Study 2 we used the microglial depletion and repopulation model mentioned above and demonstrated that the presence of infiltrating microglia-like cells following ablation could exacerbate experimental autoimmune encephalomyelitis (EAE) symptoms in Cx3cr1CreER/+Rosa26DTA/+ female mice. This was not evident in male mice, indicating a potential sex effect. Under this condition there was a higher expression of major histocompatibility complex class II and a greater secretion of proinflammatory cytokines during the acute period in the female mice.
In Study 3 we discovered a novel subpopulation of microglia that escape the genetic modification of Cx3cr1 in Cx3cr1CreER-EYFP/+Rosa26DTA/+ mice. Following microglial depletion using tamoxifen, newly repopulated Cx3cr1highEYFP– microglia had an advantage over Cx3cr1CreER-EYFP/+ and Cx3cr1lowEYFP+ microglia. We also found that microglial repopulation was tightly regulated by the CX3CL1-CX3CR1 signaling. The numbers of repopulated CNS-resident microglia were significantly decreased, while the numbers of infiltrating microglia-like cells were increased during repopulation in mice devoid of Cx3cr1.
In Study 4 we demonstrated that experimentally removing microglia using both Cx3cr1CreER/+Rosa26DTA/+ mice and PLX3397 treatment had crucial effects on circulating monocytes and splenic macrophages, a finding that had previously received little attention. We therefore proposed that clinical translation of preclinical studies using microglial depletion should take peripheral effects into consideration.
In Study 1 our results indicated that microglia could be ablated (approximately 95%) by systemic use of tamoxifen in Cx3cr1CreER/+Rosa26DTA/+ mice. Microglial repopulation ensued through both the proliferation of surviving microglia in the CNS, and from the infiltration of Ly6Chi monocytes. Under this condition infiltrating monocytes could be shaped into microglia-like cells by the CNS microenvironment. Furthermore, isolated newly repopulated resident microglia and infiltrating microglia-like cells following experimental depletion exhibited differential functionality in vitro, such as phagocytic capacity and cytokine production.
In Study 2 we used the microglial depletion and repopulation model mentioned above and demonstrated that the presence of infiltrating microglia-like cells following ablation could exacerbate experimental autoimmune encephalomyelitis (EAE) symptoms in Cx3cr1CreER/+Rosa26DTA/+ female mice. This was not evident in male mice, indicating a potential sex effect. Under this condition there was a higher expression of major histocompatibility complex class II and a greater secretion of proinflammatory cytokines during the acute period in the female mice.
In Study 3 we discovered a novel subpopulation of microglia that escape the genetic modification of Cx3cr1 in Cx3cr1CreER-EYFP/+Rosa26DTA/+ mice. Following microglial depletion using tamoxifen, newly repopulated Cx3cr1highEYFP– microglia had an advantage over Cx3cr1CreER-EYFP/+ and Cx3cr1lowEYFP+ microglia. We also found that microglial repopulation was tightly regulated by the CX3CL1-CX3CR1 signaling. The numbers of repopulated CNS-resident microglia were significantly decreased, while the numbers of infiltrating microglia-like cells were increased during repopulation in mice devoid of Cx3cr1.
In Study 4 we demonstrated that experimentally removing microglia using both Cx3cr1CreER/+Rosa26DTA/+ mice and PLX3397 treatment had crucial effects on circulating monocytes and splenic macrophages, a finding that had previously received little attention. We therefore proposed that clinical translation of preclinical studies using microglial depletion should take peripheral effects into consideration.
List of papers:
I. Competitive repopulation of an empty microglial niche yields functionally distinct subsets of microglia-like cells. Harald Lund, Melanie Pieber, Roham Parsa, Jinming Han, David Grommisch, Ewoud Ewing, Lara Kular, Maria Needhamsen, Alexander Espinosa, Emma Nilsson, Anna K. Överby, Oleg Butovsky, Maja Jagodic, Xing-Mei Zhang, Robert A. Harris. Nature Communications. 2018 Nov 19;9(1):4845.
Fulltext (DOI)
Pubmed
II. Sex-specific effects of microglia-like cell engraftment during experimental autoimmune encephalomyelitis. Jinming Han, Keying Zhu, Kai Zhou, Ramil Hakim, Sreenivasa Raghavan Sankavaram, Klas Blomgren, Harald Lund, Xing-Mei Zhang, Robert A. Harris. International Journal of Molecular Sciences. 2020 Sep 17;21(18):6824.
Fulltext (DOI)
Pubmed
III. Microglial niche repopulation competition following genetic depletion is regulated by CX3CL1-CX3CR1 signaling. Kai Zhou, Jinming Han, Harald Lund, Nageswara Rao Boggavarapu, Volker Lauschke, Shinobu Goto, Ahmed M Osman, Yuyu Wang, Asuka Tachi, Cuicui Xie, Ying Sun, Dong Liang, Wei Han, Keying Zhu, Kristina Gemzell-Danielsson, Christer Betsholtz, Xing-Mei Zhang, Changlian Zhu, Bertrand Joseph, Robert A. Harris, Klas Blomgren. [Manuscript]
IV. Underestimated peripheral effects following pharmacological and conditional genetic microglial depletion. Jinming Han, Yueshan, Fan, Kai Zhou, Keying Zhu, Klas Blomgren, Harald Lund, Xing-Mei Zhang, Robert A. Harris. International Journal of Molecular Sciences. 2020 Nov 15;21(22):8603.
Fulltext (DOI)
Pubmed
I. Competitive repopulation of an empty microglial niche yields functionally distinct subsets of microglia-like cells. Harald Lund, Melanie Pieber, Roham Parsa, Jinming Han, David Grommisch, Ewoud Ewing, Lara Kular, Maria Needhamsen, Alexander Espinosa, Emma Nilsson, Anna K. Överby, Oleg Butovsky, Maja Jagodic, Xing-Mei Zhang, Robert A. Harris. Nature Communications. 2018 Nov 19;9(1):4845.
Fulltext (DOI)
Pubmed
II. Sex-specific effects of microglia-like cell engraftment during experimental autoimmune encephalomyelitis. Jinming Han, Keying Zhu, Kai Zhou, Ramil Hakim, Sreenivasa Raghavan Sankavaram, Klas Blomgren, Harald Lund, Xing-Mei Zhang, Robert A. Harris. International Journal of Molecular Sciences. 2020 Sep 17;21(18):6824.
Fulltext (DOI)
Pubmed
III. Microglial niche repopulation competition following genetic depletion is regulated by CX3CL1-CX3CR1 signaling. Kai Zhou, Jinming Han, Harald Lund, Nageswara Rao Boggavarapu, Volker Lauschke, Shinobu Goto, Ahmed M Osman, Yuyu Wang, Asuka Tachi, Cuicui Xie, Ying Sun, Dong Liang, Wei Han, Keying Zhu, Kristina Gemzell-Danielsson, Christer Betsholtz, Xing-Mei Zhang, Changlian Zhu, Bertrand Joseph, Robert A. Harris, Klas Blomgren. [Manuscript]
IV. Underestimated peripheral effects following pharmacological and conditional genetic microglial depletion. Jinming Han, Yueshan, Fan, Kai Zhou, Keying Zhu, Klas Blomgren, Harald Lund, Xing-Mei Zhang, Robert A. Harris. International Journal of Molecular Sciences. 2020 Nov 15;21(22):8603.
Fulltext (DOI)
Pubmed
Institution: Karolinska Institutet
Supervisor: Zhang, Xing-Mei
Co-supervisor: Harris, Robert; Lund, Harald
Issue date: 2021-02-19
Rights:
Publication year: 2021
ISBN: 978-91-8016-087-2
Statistics
Total Visits
Views | |
---|---|
Repopulation ... | 962 |
Total Visits Per Month
October 2023 | November 2023 | December 2023 | January 2024 | February 2024 | March 2024 | April 2024 | |
---|---|---|---|---|---|---|---|
Repopulation ... | 27 | 24 | 13 | 17 | 28 | 29 | 15 |
File Visits
Views | |
---|---|
Thesis_Jinming_Han.pdf | 475 |
Kappa (final version).pdf | 1 |
Top country views
Views | |
---|---|
Sweden | 416 |
Ireland | 102 |
United States | 101 |
China | 82 |
Germany | 42 |
France | 15 |
Austria | 11 |
Japan | 11 |
Australia | 10 |
Finland | 10 |
Top cities views
Views | |
---|---|
Dublin | 90 |
Stockholm | 66 |
Solna | 31 |
Gothenburg | 28 |
Hangzhou | 20 |
Sundbyberg | 16 |
Örebro | 15 |
Ashburn | 14 |
Malmo | 12 |
Norrköping | 10 |