| 1. |
- Lund, Harald, et al.
(författare)
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CD163+ macrophages monitor enhanced permeability at the blood-dorsal root ganglion barrier
- 2024
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Ingår i: Journal of Experimental Medicine. - : Rockefeller University Press. - 0022-1007 .- 1540-9538. ; 221:2
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Tidskriftsartikel (refereegranskat)abstract
- In dorsal root ganglia (DRG), macrophages reside close to sensory neurons and have largely been explored in the context of pain, nerve injury, and repair. However, we discovered that most DRG macrophages interact with and monitor the vasculature by sampling macromolecules from the blood. Characterization of the DRG vasculature revealed a specialized endothelial bed that transformed in molecular, structural, and permeability properties along the arteriovenous axis and was covered by macrophage-interacting pericytes and fibroblasts. Macrophage phagocytosis spatially aligned with peak endothelial permeability, a process regulated by enhanced caveolar transcytosis in endothelial cells. Profiling the DRG immune landscape revealed two subsets of perivascular macrophages with distinct transcriptome, turnover, and function. CD163(+) macrophages self-maintained locally, specifically participated in vasculature monitoring, displayed distinct responses during peripheral inflammation, and were conserved in mouse and man. Our work provides a molecular explanation for the permeability of the blood-DRG barrier and identifies an unappreciated role of macrophages as integral components of the DRG-neurovascular unit.
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| 2. |
- Rangasami, Vignesh K., et al.
(författare)
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Harnessing hyaluronic acid-based nanoparticles for combination therapy : A novel approach for suppressing systemic inflammation and to promote antitumor macrophage polarization
- 2021
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Ingår i: Carbohydrate Polymers. - : Elsevier. - 0144-8617 .- 1879-1344. ; 254
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Tidskriftsartikel (refereegranskat)abstract
- Anti-inflammatory drugs such as dexamethasone (DEX) are commonly administered to cancer patients along with anticancer drugs, however, the effect of DEX on human cancers is poorly understood. In this article, we have tailored self-assembled nanoparticles derived from hyaluronic acid (HA) wherein, anti-inflammatory DEX was used as a hydrophobic moiety for inducing amphiphilicity. The HA-DEX micelles were subsequently loaded with chemotherapeutic agent, doxorubicin (DOX) (HA-DEX-DOX) and was utilized to deliver drug cargo to human cancer cells expressing different levels of CD44 receptors. We found that DEX suppressed the cytotoxicity of DOX in HCT116, while it synergistically enhanced cytotoxicity in MCF-7 cells. When we tested DOX and HA-DEX-DOX in an ex-vivo human whole blood, we found activation of complement and the coagulation cascade in one group of donors. Encapsulation of DOX within the nanoparticle core eliminated such deleterious side-effects. The HADEX-DOX also polarized bone-marrow-derived anti-inflammatory M2 macrophages, to pro-inflammatory M1 phenotype with the upregulation of the cytokines TNF-alpha, iNOS and IL-1 beta.
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| 3. |
- Zhu, Keying
(författare)
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Deciphering and fine-tuning of myeloid cells in CNS demyelinating conditions
- 2023
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Demyelination in the central nervous system (CNS) is a characteristic of various neurological disorders, such as multiple sclerosis (MS), neuromyelitis optica (NMO), subacute combined degeneration (SCD), tabes dorsalis (syphilitic myelopathy), and more. Although the causes vary, CNS demyelination is often associated with a significant buildup of inflammatory activated myeloid cells, mainly consisting of CNS resident microglia and infiltrating monocyte-derived macrophages. On one hand, these myeloid cells can contribute to inflammation in the CNS and damage myelin, but on the other hand, they play a role in clearing myelin debris and releasing substances that facilitate myelin regeneration, a process known as remyelination. Therefore, it is crucial to determine the signals that control their specific functions and develop methods for regulating their activity. In this thesis, we investigated the role of TGF-β signaling in regulating myeloid cell function. By using cell-specific targeting mouse tools, we discovered that when the CNS lacks microglia in a specific experimental setting, where peripheral monocytes can enter the CNS and repopulate the microglia pool by transforming into microglia-like macrophages, deleting the TGF-β receptor (TGFBR2) on monocytes prevents their entry into the CNS. Furthermore, when monocyte-derived macrophages are engrafted in the CNS, the depletion of TGFBR2 causes their abnormal activation and failure to adopt a microglia-like signature, leading to spontaneous demyelination in the spinal cord and a progressive, fatal motor disease. The loss of TGF- β signaling in microglia or monocyte-derived microglia-like cells preferentially targets myelin in the dorsal column of the spinal cord, and a subpopulation of microglia closely associated with myelin loss is identified in the dorsal column. We further characterized that this microglial TGF-β signaling loss-induced disease is more severe in female and older mice and uncovered potential molecular mechanisms underlying these gender and age differences in response to the loss of TGF-β signaling. In addition to deciphering the mechanisms governing myeloid function, we also conducted translational studies aiming to provide therapeutic insights for demyelinating diseases. By using a drug screening tool and performing in vitro validation, as well as experiments in mouse models with CNS inflammation and ensuing demyelination, we confirmed the regulatory effect of topotecan, a topoisomerase 1 inhibitor, on myeloid cells, leading to improved disease outcome. We further developed a DNA nanostructure-based drug delivery system to encapsule topotecan and achieve specific targeting of TOP1 in myeloid cells, demonstrating that myeloid cell-specific inhibition of TOP1 could alleviate neuroinflammation. In the final study, within a non-inflammation-driven demyelinating context, we studied the role of TRPV1 activation in remyelination and revealed that the TRPV1 activator capsaicin could enhance microglial clearance of myelin debris following demyelination and promote remyelination. My thesis work thus provides mechanistic understanding of how myeloid cells regulate myelin health and CNS homeostasis, while also providing regulatory strategies for fine-tuning these cells.
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