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JOURNAL ARTICLE
Dong-Oh Seo, David O'Donnell, Nimansha Jain, Jason D Ulrich, Jasmin Herz, Yuhao Li, Mackenzie Lemieux, Jiye Cheng, Hao Hu, Javier R Serrano, Xin Bao, Emily Franke, Maria Karlsson, Martin Meier, Su Deng, Chandani Desai, Hemraj Dodiya, Janaki Lelwala-Guruge, Scott A Handley, Jonathan Kipnis, Sangram S Sisodia, Jeffrey I Gordon, David M Holtzman
Tau-mediated neurodegeneration is a hallmark of Alzheimer's disease. Primary tauopathies are characterized by pathological tau accumulation and neuronal and synaptic loss. Apolipoprotein E (ApoE)-mediated neuroinflammation is involved in the progression of tau-mediated neurodegeneration, and emerging evidence suggests that the gut microbiota regulates neuroinflammation in an APOE genotype-dependent manner. However, evidence of a causal link between the microbiota and tau-mediated neurodegeneration is lacking...
January 13, 2023: Science
#22
REVIEW
Justin Rustenhoven, Jonathan Kipnis
The concept of immune privilege suggests that the central nervous system is isolated from the immune system. However, recent studies have highlighted the borders of the central nervous system as central sites of neuro-immune interactions. Although the nervous and immune systems both function to maintain homeostasis, under rare circumstances, they can develop pathological interactions that lead to neurological or psychiatric diseases. Here we discuss recent findings that dissect the key anatomical, cellular and molecular mechanisms that enable neuro-immune responses at the borders of the brain and spinal cord and the implications of these interactions for diseases of the central nervous system...
December 2022: Nature
#23
JOURNAL ARTICLE
Antoine Drieu, Siling Du, Steffen E Storck, Justin Rustenhoven, Zachary Papadopoulos, Taitea Dykstra, Fenghe Zhong, Kyungdeok Kim, Susan Blackburn, Tornike Mamuladze, Oscar Harari, Celeste M Karch, Randall J Bateman, Richard Perrin, Martin Farlow, Jasmeer Chhatwal, Song Hu, Gwendalyn J Randolph, Igor Smirnov, Jonathan Kipnis
Macrophages are important players in the maintenance of tissue homeostasis1 . Perivascular and leptomeningeal macrophages reside near the central nervous system (CNS) parenchyma2 , and their role in CNS physiology has not been sufficiently well studied. Given their continuous interaction with the cerebrospinal fluid (CSF) and strategic positioning, we refer to these cells collectively as parenchymal border macrophages (PBMs). Here we demonstrate that PBMs regulate CSF flow dynamics. We identify a subpopulation of PBMs that express high levels of CD163 and LYVE1 (scavenger receptor proteins), closely associated with the brain arterial tree, and show that LYVE1+ PBMs regulate arterial motion that drives CSF flow...
November 9, 2022: Nature
#24
REVIEW
Rosa C Paolicelli, Amanda Sierra, Beth Stevens, Marie-Eve Tremblay, Adriano Aguzzi, Bahareh Ajami, Ido Amit, Etienne Audinat, Ingo Bechmann, Mariko Bennett, Frederick Bennett, Alain Bessis, Knut Biber, Staci Bilbo, Mathew Blurton-Jones, Erik Boddeke, Dora Brites, Bert Brône, Guy C Brown, Oleg Butovsky, Monica J Carson, Bernardo Castellano, Marco Colonna, Sally A Cowley, Colm Cunningham, Dimitrios Davalos, Philip L De Jager, Bart de Strooper, Adam Denes, Bart J L Eggen, Ukpong Eyo, Elena Galea, Sonia Garel, Florent Ginhoux, Christopher K Glass, Ozgun Gokce, Diego Gomez-Nicola, Berta González, Siamon Gordon, Manuel B Graeber, Andrew D Greenhalgh, Pierre Gressens, Melanie Greter, David H Gutmann, Christian Haass, Michael T Heneka, Frank L Heppner, Soyon Hong, David A Hume, Steffen Jung, Helmut Kettenmann, Jonathan Kipnis, Ryuta Koyama, Greg Lemke, Marina Lynch, Ania Majewska, Marzia Malcangio, Tarja Malm, Renzo Mancuso, Takahiro Masuda, Michela Matteoli, Barry W McColl, Veronique E Miron, Anna Victoria Molofsky, Michelle Monje, Eva Mracsko, Agnes Nadjar, Jonas J Neher, Urte Neniskyte, Harald Neumann, Mami Noda, Bo Peng, Francesca Peri, V Hugh Perry, Phillip G Popovich, Clare Pridans, Josef Priller, Marco Prinz, Davide Ragozzino, Richard M Ransohoff, Michael W Salter, Anne Schaefer, Dorothy P Schafer, Michal Schwartz, Mikael Simons, Cody J Smith, Wolfgang J Streit, Tuan Leng Tay, Li-Huei Tsai, Alexei Verkhratsky, Rommy von Bernhardi, Hiroaki Wake, Valérie Wittamer, Susanne A Wolf, Long-Jun Wu, Tony Wyss-Coray
Microglial research has advanced considerably in recent decades yet has been constrained by a rolling series of dichotomies such as "resting versus activated" and "M1 versus M2." This dualistic classification of good or bad microglia is inconsistent with the wide repertoire of microglial states and functions in development, plasticity, aging, and diseases that were elucidated in recent years. New designations continuously arising in an attempt to describe the different microglial states, notably defined using transcriptomics and proteomics, may easily lead to a misleading, although unintentional, coupling of categories and functions...
November 2, 2022: Neuron
#25
JOURNAL ARTICLE
(no author information available yet)
In an interview with Neuron, Jony Kipnis discusses his formative academic years and subsequent discoveries in meningeal lymphatics. He is enthusiastic about the prospect of therapeutic developments in neuroimmunology arising from focusing on the brain's borders.
November 2, 2022: Neuron
#26
JOURNAL ARTICLE
Xinan Chen, Xiaodan Liu, Sunil Koundal, Rena Elkin, Xiaoyue Zhu, Brittany Monte, Feng Xu, Feng Dai, Maysam Pedram, Hedok Lee, Jonathan Kipnis, Allen Tannenbaum, William E Van Nostrand, Helene Benveniste
No abstract text is available yet for this article.
March 2022: Nature aging
#27
JOURNAL ARTICLE
Aymeric Silvin, Stefan Uderhardt, Cecile Piot, Sandro Da Mesquita, Katharine Yang, Laufey Geirsdottir, Kevin Mulder, David Eyal, Zhaoyuan Liu, Cecile Bridlance, Morgane Sonia Thion, Xiao Meng Zhang, Wan Ting Kong, Marc Deloger, Vasco Fontes, Assaf Weiner, Rachel Ee, Regine Dress, Jing Wen Hang, Akhila Balachander, Svetoslav Chakarov, Benoit Malleret, Garett Dunsmore, Olivier Cexus, Jinmiao Chen, Sonia Garel, Charles Antoine Dutertre, Ido Amit, Jonathan Kipnis, Florent Ginhoux
Brain macrophage populations include parenchymal microglia, border-associated macrophages, and recruited monocyte-derived cells; together, they control brain development and homeostasis but are also implicated in aging pathogenesis and neurodegeneration. The phenotypes, localization, and functions of each population in different contexts have yet to be resolved. We generated a murine brain myeloid scRNA-seq integration to systematically delineate brain macrophage populations. We show that the previously identified disease-associated microglia (DAM) population detected in murine Alzheimer's disease models actually comprises two ontogenetically and functionally distinct cell lineages: embryonically derived triggering receptor expressed on myeloid cells 2 (TREM2)-dependent DAM expressing a neuroprotective signature and monocyte-derived TREM2-expressing disease inflammatory macrophages (DIMs) accumulating in the brain during aging...
August 4, 2022: Immunity
#28
REVIEW
Andrea Francesca M Salvador, Jonathan Kipnis
Traumatic injuries of the central nervous system (CNS) affect millions of people worldwide, and they can lead to severely damaging consequences such as permanent disability and paralysis. Multiple factors can obstruct recovery after CNS injury. One of the most significant is the progressive neuronal death that follows the initial mechanical impact, leading to the loss of undamaged cells via a process termed secondary neurodegeneration. Efforts to define treatments that limit the spread of damage, while important, have been largely ineffectual owing to gaps in the mechanistic understanding that underlies the persisting neuronal cell death...
January 2022: Seminars in Immunology
#29
Noël C Derecki, Jonathan Kipnis
No abstract text is available yet for this article.
February 2022: Nature Neuroscience
#30
JOURNAL ARTICLE
Steven M Blum, William R Jeck, Lindsay Kipnis, Ronald Bleday, Jonathan A Nowak, Matthew B Yurgelun
Two major molecular pathways of colorectal carcinogenesis, chromosomal instability (CIN) and microsatellite instability (MSI), are considered to be mutually exclusive. Distinguishing CIN from MSI-high tumors has considerable therapeutic implications, because patients with MSI-high tumors can derive considerable benefit from immune checkpoint inhibitors, and tumors that evolved through the CIN pathway do not respond to these agents. Familial adenomatous polyposis (FAP) is a genetic syndrome that is defined by a mutation in the APC gene and is thought to lead to carcinogenesis through the CIN pathway...
December 2021: Journal of the National Comprehensive Cancer Network: JNCCN
#31
JOURNAL ARTICLE
Jasmin Herz, Zhongxiao Fu, Kyungdeok Kim, Taitea Dykstra, Morgan Wall, Huiping Li, Andrea Francesca Salvador, Bende Zou, Ni Yan, Susan M Blackburn, Patrick H Andrews, Dylan H Goldman, Zachary Papadopoulos, Igor Smirnov, Xinmin S Xie, Jonathan Kipnis
Mechanisms governing how immune cells and their derived molecules impact homeostatic brain function are still poorly understood. Here, we elucidate neuronal mechanisms underlying T cell effects on synaptic function and episodic memory. Depletion of CD4 T cells led to memory deficits and impaired long-term potentiation. Severe combined immune-deficient mice exhibited amnesia, which was reversible by repopulation with T cells from wild-type but not from IL-4-knockout mice. Behaviors impacted by T cells were mediated via IL-4 receptors expressed on neurons...
November 17, 2021: Neuron
#32
LETTER
Jonathan Kipnis
No abstract text is available yet for this article.
August 2021: Nature
#33
COMMENT
Hellmut G Augustin, Jonathan Kipnis
No abstract text is available yet for this article.
July 30, 2021: Science
#34
REVIEW
Justin Rustenhoven, Catherine Tanumihardja, Jonathan Kipnis
Appropriate vascular function is essential for the maintenance of central nervous system homeostasis and is achieved through virtue of the blood-brain barrier; a specialized structure consisting of endothelial, mural, and astrocytic interactions. While appropriate blood-brain barrier function is typically achieved, the central nervous system vasculature is not infallible and cerebrovascular anomalies, a collective terminology for diverse vascular lesions, are present in meningeal and cerebral vasculature supplying and draining the brain...
June 25, 2021: Circulation Research
#35
JOURNAL ARTICLE
Simone Brioschi, Wei-Le Wang, Vincent Peng, Meng Wang, Irina Shchukina, Zev J Greenberg, Jennifer K Bando, Natalia Jaeger, Rafael S Czepielewski, Amanda Swain, Denis A Mogilenko, Wandy L Beatty, Peter Bayguinov, James A J Fitzpatrick, Laura G Schuettpelz, Catrina C Fronick, Igor Smirnov, Jonathan Kipnis, Virginia S Shapiro, Gregory F Wu, Susan Gilfillan, Marina Cella, Maxim N Artyomov, Steven H Kleinstein, Marco Colonna
The meninges contain adaptive immune cells that provide immunosurveillance of the central nervous system (CNS). These cells are thought to derive from the systemic circulation. Through single-cell analyses, confocal imaging, bone marrow chimeras, and parabiosis experiments, we show that meningeal B cells derive locally from the calvaria, which harbors a bone marrow niche for hematopoiesis. B cells reach the meninges from the calvaria through specialized vascular connections. This calvarial-meningeal path of B cell development may provide the CNS with a constant supply of B cells educated by CNS antigens...
July 23, 2021: Science
#36
JOURNAL ARTICLE
Andrea Cugurra, Tornike Mamuladze, Justin Rustenhoven, Taitea Dykstra, Giorgi Beroshvili, Zev J Greenberg, Wendy Baker, Zach Papadopoulos, Antoine Drieu, Susan Blackburn, Mitsuhiro Kanamori, Simone Brioschi, Jasmin Herz, Laura G Schuettpelz, Marco Colonna, Igor Smirnov, Jonathan Kipnis
The meninges are a membranous structure enveloping the central nervous system (CNS) that host a rich repertoire of immune cells mediating CNS immune surveillance. Here, we report that the mouse meninges contain a pool of monocytes and neutrophils supplied not from the blood but by adjacent skull and vertebral bone marrow. Under pathological conditions, including spinal cord injury and neuroinflammation, CNS-infiltrating myeloid cells can originate from brain borders and display transcriptional signatures distinct from their blood-derived counterparts...
July 23, 2021: Science
#37
JOURNAL ARTICLE
Sandro Da Mesquita, Jasmin Herz, Morgan Wall, Taitea Dykstra, Kalil Alves de Lima, Geoffrey T Norris, Nisha Dabhi, Tatiana Kennedy, Wendy Baker, Jonathan Kipnis
Aging leads to a progressive deterioration of meningeal lymphatics and peripheral immunity, which may accelerate cognitive decline. We hypothesized that an age-related reduction in C-C chemokine receptor type 7 (CCR7)-dependent egress of immune cells through the lymphatic vasculature mediates some aspects of brain aging and potentially exacerbates cognitive decline and Alzheimer's disease-like brain β-amyloid (Aβ) pathology. We report a reduction in CCR7 expression by meningeal T cells in old mice that is linked to increased effector and regulatory T cells...
May 2021: Science Advances
#38
JOURNAL ARTICLE
Sandro Da Mesquita, Zachary Papadopoulos, Taitea Dykstra, Logan Brase, Fabiana Geraldo Farias, Morgan Wall, Hong Jiang, Chinnappa Dilip Kodira, Kalil Alves de Lima, Jasmin Herz, Antoine Louveau, Dylan H Goldman, Andrea Francesca Salvador, Suna Onengut-Gumuscu, Emily Farber, Nisha Dabhi, Tatiana Kennedy, Mary Grace Milam, Wendy Baker, Igor Smirnov, Stephen S Rich, Bruno A Benitez, Celeste M Karch, Richard J Perrin, Martin Farlow, Jasmeer P Chhatwal, David M Holtzman, Carlos Cruchaga, Oscar Harari, Jonathan Kipnis
Alzheimer's disease (AD) is the most prevalent cause of dementia1 . Although there is no effective treatment for AD, passive immunotherapy with monoclonal antibodies against amyloid beta (Aβ) is a promising therapeutic strategy2,3 . Meningeal lymphatic drainage has an important role in the accumulation of Aβ in the brain4 , but it is not known whether modulation of meningeal lymphatic function can influence the outcome of immunotherapy in AD. Here we show that ablation of meningeal lymphatic vessels in 5xFAD mice (a mouse model of amyloid deposition that expresses five mutations found in familial AD) worsened the outcome of mice treated with anti-Aβ passive immunotherapy by exacerbating the deposition of Aβ, microgliosis, neurovascular dysfunction, and behavioural deficits...
May 2021: Nature
#39
REVIEW
Andrea Francesca Salvador, Kalil Alves de Lima, Jonathan Kipnis
Interactions between the immune system and the nervous system have been described mostly in the context of diseases. More recent studies have begun to reveal how certain immune cell-derived soluble effectors, the cytokines, can influence host behaviour even in the absence of infection. In this Review, we contemplate how the immune system shapes nervous system function and how it controls the manifestation of host behaviour. Interactions between these two highly complex systems are discussed here also in the context of evolution, as both may have evolved to maximize an organism's ability to respond to environmental threats in order to survive...
August 2021: Nature Reviews. Immunology
#40
JOURNAL ARTICLE
Justin Rustenhoven, Antoine Drieu, Tornike Mamuladze, Kalil Alves de Lima, Taitea Dykstra, Morgan Wall, Zachary Papadopoulos, Mitsuhiro Kanamori, Andrea Francesca Salvador, Wendy Baker, Mackenzie Lemieux, Sandro Da Mesquita, Andrea Cugurra, James Fitzpatrick, Sanja Sviben, Ross Kossina, Peter Bayguinov, Reid R Townsend, Qiang Zhang, Petra Erdmann-Gilmore, Igor Smirnov, Maria-Beatriz Lopes, Jasmin Herz, Jonathan Kipnis
Despite the established dogma of central nervous system (CNS) immune privilege, neuroimmune interactions play an active role in diverse neurological disorders. However, the precise mechanisms underlying CNS immune surveillance remain elusive; particularly, the anatomical sites where peripheral adaptive immunity can sample CNS-derived antigens and the cellular and molecular mediators orchestrating this surveillance. Here, we demonstrate that CNS-derived antigens in the cerebrospinal fluid (CSF) accumulate around the dural sinuses, are captured by local antigen-presenting cells, and are presented to patrolling T cells...
February 18, 2021: Cell
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