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Neuroinflammation during stroke and Gaucher’s disease : How monocyte-derived macrophages and microglia shape the inflammatory environment of the brain

Tampe, Juliane LU orcid (2025) In Lund University, Faculty of Medicine Doctoral Dissertation Series
Abstract
The human brain is a complex and finely tuned organ, constantly monitored and maintained by its resident immune cells.
Among these, microglia are the primary regulators of the brain immune environment under physiological conditions, and monocyte-derived macrophages contribute mainly to pathological states such as ischemic stroke and neuronopathic Gaucher’s disease (GD). These two diseases, although different in origin, one acute and vascular, the other chronic and genetic, share a common feature: a disruption in immune homeostasis marked by neuroinflammation.
Using flow cytometry, gene expression profiling, and induced pluripotent stem cell (iPSC)-derived cell modeling, this work demonstrated that monocytes and microglia are... (More)
The human brain is a complex and finely tuned organ, constantly monitored and maintained by its resident immune cells.
Among these, microglia are the primary regulators of the brain immune environment under physiological conditions, and monocyte-derived macrophages contribute mainly to pathological states such as ischemic stroke and neuronopathic Gaucher’s disease (GD). These two diseases, although different in origin, one acute and vascular, the other chronic and genetic, share a common feature: a disruption in immune homeostasis marked by neuroinflammation.
Using flow cytometry, gene expression profiling, and induced pluripotent stem cell (iPSC)-derived cell modeling, this work demonstrated that monocytes and microglia are dynamically regulated by intrinsic factors and extrinsic stimuli. During human aging, circulating monocyte subsets undergo sex-dependent transcriptional remodeling, with females exhibiting stronger anti-inflammatory aging signatures. This was particularly evident in the upregulation of ANXA1 in female non-classical monocytes. Additionally, age-associated increases in the scavenger receptor CD36 were observed across all monocyte subtypes.
In ischemic stroke patients, monocyte frequency and gene expression patterns predict recovery, particularly through the expansion of intermediate monocytes and the downregulation of inflammatory mediators. A panel of recovery-associated markers: CD91, CD36, TGM2, SLC24A4, and CD38, were identified, with CD36 in intermediate monocytes emerging as a novel marker of recovery.
In neuronopathic GD, human iPSC-derived microglia (hiMG) exhibit intrinsic impairments in cytokine signaling and lysosomal function under immune stimulation, indicating chronic neuroimmune dysfunction. These changes suggest a brain-specific immune phenotype distinct from peripheral macrophages and support a role for microglia in GD-associated neurodegeneration.
In summary, this thesis explores how peripheral monocytes and brain-resident microglia, both part of the mononuclear phagocyte system, shape the neuroinflammatory processes during aging, ischemic stroke, and GD. It highlights how immune responses are influenced by age, sex, and disease state, providing mechanistic insight and models for developing future immune-targeted therapies for neurological diseases. (Less)
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author
supervisor
opponent
  • Associate Professor Lambertsen, Kate Lykke, University of Southern Denmark and Odense University Hospital
organization
publishing date
type
Thesis
publication status
published
subject
keywords
Monocytes, Stroke, Gene expression, Neuroinflammation, Recovery, iPSC-derived microglia, Gaucher's disease, Lysosomal dysfunction, Disease modeling
in
Lund University, Faculty of Medicine Doctoral Dissertation Series
issue
2025:91
pages
107 pages
publisher
Lund University, Faculty of Medicine
defense location
Segerfalksalen, BMC A10, Sölvegatan 17 i Lund
defense date
2025-09-18 09:00:00
ISSN
1652-8220
ISBN
978-91-8021-744-6
project
Characterisation of human monocytes for age and gender signatures and during stroke
language
English
LU publication?
yes
id
f64dd14b-39d2-4254-b73d-db1f3c698b45
date added to LUP
2025-08-28 15:05:09
date last changed
2025-08-29 10:06:09
@phdthesis{f64dd14b-39d2-4254-b73d-db1f3c698b45,
  abstract     = {{The human brain is a complex and finely tuned organ, constantly monitored and maintained by its resident immune cells.<br/>Among these, microglia are the primary regulators of the brain immune environment under physiological conditions, and monocyte-derived macrophages contribute mainly to pathological states such as ischemic stroke and neuronopathic Gaucher’s disease (GD). These two diseases, although different in origin, one acute and vascular, the other chronic and genetic, share a common feature: a disruption in immune homeostasis marked by neuroinflammation.<br/>Using flow cytometry, gene expression profiling, and induced pluripotent stem cell (iPSC)-derived cell modeling, this work demonstrated that monocytes and microglia are dynamically regulated by intrinsic factors and extrinsic stimuli. During human aging, circulating monocyte subsets undergo sex-dependent transcriptional remodeling, with females exhibiting stronger anti-inflammatory aging signatures. This was particularly evident in the upregulation of ANXA1 in female non-classical monocytes. Additionally, age-associated increases in the scavenger receptor CD36 were observed across all monocyte subtypes.<br/>In ischemic stroke patients, monocyte frequency and gene expression patterns predict recovery, particularly through the expansion of intermediate monocytes and the downregulation of inflammatory mediators. A panel of recovery-associated markers: CD91, CD36, TGM2, SLC24A4, and CD38, were identified, with CD36 in intermediate monocytes emerging as a novel marker of recovery.<br/>In neuronopathic GD, human iPSC-derived microglia (hiMG) exhibit intrinsic impairments in cytokine signaling and lysosomal function under immune stimulation, indicating chronic neuroimmune dysfunction. These changes suggest a brain-specific immune phenotype distinct from peripheral macrophages and support a role for microglia in GD-associated neurodegeneration.<br/>In summary, this thesis explores how peripheral monocytes and brain-resident microglia, both part of the mononuclear phagocyte system, shape the neuroinflammatory processes during aging, ischemic stroke, and GD. It highlights how immune responses are influenced by age, sex, and disease state, providing mechanistic insight and models for developing future immune-targeted therapies for neurological diseases.}},
  author       = {{Tampe, Juliane}},
  isbn         = {{978-91-8021-744-6}},
  issn         = {{1652-8220}},
  keywords     = {{Monocytes; Stroke; Gene expression; Neuroinflammation; Recovery; iPSC-derived microglia; Gaucher's disease; Lysosomal dysfunction; Disease modeling}},
  language     = {{eng}},
  number       = {{2025:91}},
  publisher    = {{Lund University, Faculty of Medicine}},
  school       = {{Lund University}},
  series       = {{Lund University, Faculty of Medicine Doctoral Dissertation Series}},
  title        = {{Neuroinflammation during stroke and Gaucher’s disease : How monocyte-derived macrophages and microglia shape the inflammatory environment of the brain}},
  url          = {{https://lup.lub.lu.se/search/files/226456085/e-nailing_ex_Tampe.pdf}},
  year         = {{2025}},
}