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[230915 저널발표] Infiltrating CD8+ T cells exacerbate Alzheimer’s disease pathology in a 3D human neuroimmune axis model
Nat Neurosci. 2023 Sep;26(9):1489-1504. doi: 10.1038/s41593-023-01415-3. Epub 2023 Aug 24.Infiltrating CD8+ T cells exacerbate Alzheimer's disease pathology in a 3D human neuroimmune axis modelMehdi Jorfi # 1 2 3, Joseph Park # 4 5, Clare K Hall 4, Chih-Chung Jerry Lin 4, Meng Chen 4, Djuna von Maydell 4, Jane M Kruskop 4, Byunghoon Kang 4, Younjung Choi 4, Dmitry Prokopenko 4 5, Daniel Irimia 5 6 7, Doo Yeon Kim 8 9, Rudolph E Tanzi 10 11Affiliations expandPMID: 37620442 DOI: 10.1038/s41593-023-01415-3AbstractBrain infiltration of peripheral immune cells and their interactions with brain-resident cells may contribute to Alzheimer's disease (AD) pathology. To examine these interactions, in the present study we developed a three-dimensional human neuroimmune axis model comprising stem cell-derived neurons, astrocytes and microglia, together with peripheral immune cells. We observed an increase in the number of T cells (but not B cells) and monocytes selectively infiltrating into AD relative to control cultures. Infiltration of CD8+ T cells into AD cultures led to increased microglial activation, neuroinflammation and neurodegeneration. Using single-cell RNA-sequencing, we identified that infiltration of T cells into AD cultures led to induction of interferon-γ and neuroinflammatory pathways in glial cells. We found key roles for the C-X-C motif chemokine ligand 10 (CXCL10) and its receptor, CXCR3, in regulating T cell infiltration and neuronal damage in AD cultures. This human neuroimmune axis model is a useful tool to study the effects of peripheral immune cells in brain disease. 2023.09.13 -
[230915 저널발표] PET imaging of TREM1 identifies CNS-infiltrating myeloid cells in a mouse model of multiple sclerosis
Sci Transl Med. 2023 Jun 28;15(702):eabm6267. doi: 10.1126/scitranslmed.abm6267. Epub 2023 Jun 28.PET imaging of TREM1 identifies CNS-infiltrating myeloid cells in a mouse model of multiple sclerosisAisling M Chaney 1 2, Haley C Cropper 1, Poorva Jain 1, Edward Wilson 3, Federico Simonetta 5, Emily M Johnson 1, Israt S Alam 1, Ian T J Patterson 1, Michelle Swarovski 3, Marc Y Stevens 1, Qian Wang 3, Carmen Azevedo 1, Sydney C Nagy 1, Javier Ramos Benitez 3, Emily M Deal 1, Hannes Vogel 6, Katrin I Andreasson 3 7, Michelle L James 1 3Affiliations expandPMID: 37379371 DOI: 10.1126/scitranslmed.abm6267AbstractMultiple sclerosis (MS) is an immune-mediated demyelinating disease of the central nervous system (CNS) that causes substantial morbidity and diminished quality of life. Evidence highlights the central role of myeloid lineage cells in the initiation and progression of MS. However, existing imaging strategies for detecting myeloid cells in the CNS cannot distinguish between beneficial and harmful immune responses. Thus, imaging strategies that specifically identify myeloid cells and their activation states are critical for MS disease staging and monitoring of therapeutic responses. We hypothesized that positron emission tomography (PET) imaging of triggering receptor expressed on myeloid cells 1 (TREM1) could be used to monitor deleterious innate immune responses and disease progression in the experimental autoimmune encephalomyelitis (EAE) mouse model of MS. We first validated TREM1 as a specific marker of proinflammatory, CNS-infiltrating, peripheral myeloid cells in mice with EAE. We show that the 64Cu-radiolabeled TREM1 antibody-based PET tracer monitored active disease with 14- to 17-fold higher sensitivity than translocator protein 18 kDa (TSPO)-PET imaging, the established approach for detecting neuroinflammation in vivo. We illustrate the therapeutic potential of attenuating TREM1 signaling both genetically and pharmacologically in the EAE mice and show that TREM1-PET imaging detected responses to an FDA-approved MS therapy with siponimod (BAF312) in these animals. Last, we observed TREM1+ cells in clinical brain biopsy samples from two treatment-na 2023.09.13