Neuroimmunology: To Sense and Protect Eugene M. Oltz J Immunol 2020; 204:239-240; ; This information is current as doi: 10.4049/jimmunol.1990024 of September 24, 2021. http://www.jimmunol.org/content/204/2/239 Downloaded from References This article cites 11 articles, 11 of which you can access for free at: http://www.jimmunol.org/content/204/2/239.full#ref-list-1 Why The JI? Submit online. http://www.jimmunol.org/ • Rapid Reviews! 30 days* from submission to initial decision • No Triage! Every submission reviewed by practicing scientists • Fast Publication! 4 weeks from acceptance to publication *average by guest on September 24, 2021 Subscription Information about subscribing to The Journal of Immunology is online at: http://jimmunol.org/subscription Permissions Submit copyright permission requests at: http://www.aai.org/About/Publications/JI/copyright.html Email Alerts Receive free email-alerts when new articles cite this article. Sign up at: http://jimmunol.org/alerts The Journal of Immunology is published twice each month by The American Association of Immunologists, Inc., 1451 Rockville Pike, Suite 650, Rockville, MD 20852 Copyright © 2020 by The American Association of Immunologists, Inc. All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. Neuroimmunology: To Sense and Protect he influence of the CNS and peripheral nervous system (PNS) on immune health, and vice versa, has T been a central theme of health, science, and folklore for centuries. People have long suspected that stress en- hances our susceptibility to infections and promotes episodes of autoimmunity. On the flip side, Cox2 inhibitors amelio- rate both immune-based inflammation and neural-based pain. Clinicians also noted that denervation can stem the progres- sion of rheumatoid arthritis or psoriasis, suggesting that sen- sory neurons might fuel some aspects of inflammation. However, cross-talk between the neural and immune sys- Downloaded from tems, which are so central to human health and disease, was difficult to assess and, until recently, neuroimmunology was relegated to the final sessions of many conferences. This backwater status has taken a dramatic about-face in recent years because of a number of watershed discoveries. These include our realization that Alzheimer disease (AD) and other neurode- Confocal micrograph showcasing meningeal lymphatic vessels along the http://www.jimmunol.org/ generative conditions are propagated by inflammation, with some superior sagittal sinus using tdTomato driven by the Prox1 promoter, of the neuronal destruction occurring through actions of immune shown in yellow. Macrophages are stained with Iba1 in magenta, and cells within the CNS. T cells are shown in cyan using CD3 as a marker. Iba1-positive cells are spread throughout the meningeal whole mount, whereas CD3-positive As with many revolutions, the emergence of neuro- T cells are frequently found in close association with lymphatic vessels immunology as a prominent field came with technical as well as distributed throughout the meninges. Image provided by advances that now permit a more holistic approach to study Jonathan Kipnis, University of Virginia. dialogue between the immune system and other organ systems. Breakthroughs in multiparameter cytometry, imaging, and by guest on September 24, 2021 single-cell sequencing technologies have begun to unravel, two systems, which they call the “neuroimmune interactome.” with an unprecedented resolution, the diversity of cells, their Next, Kaplan and colleagues (2) delve into a more specific locations, and molecular functions that orchestrate the immune– aspect of neuroimmune cross-talk: neuronal regulation of neural interface. cutaneous immunity. As discussedinbothreviews,thePNS Given the palpable excitement and the rapid proliferation of and immune systems serve as sentinels for invading patho- papers in the field, I felt that it would be timely for the fourth gens, with barrier tissues, such as the skin, being rich in annual issue of topical reviews to focus on neuroimmunology. immune cells and nociceptors, sensory neurons that detect I am proud to introduce “Neuroimmunology: To Sense and noxious agents or dangerous pathogens by producing pain Protect”—a collection of 11 reviews, including a Translating or itch sensations. Both the Woolf and Kaplan reviews high- Immunology review and a Pillars of Immunology commentary. light the multitude of molecules produced by neurons and It is my hope that this collection will provide our readers with immune cells to communicate danger to each other (e.g., a broad perspective on not only the healthy dialogue be- cytokines, chemokines, and neuropeptides) and by which tween immune and neural cells, which maintains homeo- neurons can sense pathogens (e.g., TLRs). stasis in both systems, but also how the wrong conversations Henneke and colleagues (3) next discuss how immune cells or overreaction of one system can trigger a variety of patho- communicate with the PNS to discriminate between healthy logical conditions, ranging from chronic pain to autoimmu- and damaged neurons. The authors discuss the variety of em- nity to loss of neural function. bryonically derived macrophages that associate with peripheral The first portion of this special collection focuses on the neurons. These cells not only may contribute to axon guidance, interplay between the immune system and the PNS. Woolf homeostasis, and nerve regeneration but also can cause damage and colleagues (1) begin the collection with an overview of following an infection or trauma. The codependent mecha- the plasticity present in both systems, highlighting the “sense nisms may be especially relevant to peripheral nerve diseases, and protect” theme. They also provide a thoughtful discussion including diabetic neuropathy and chronic pain. of how to prioritize approaches that will yield a deeper un- Another emerging theme in neuroimmunology is the im- derstanding of receptor–ligand communication between the portant role that neurons may play in in the tumor micro- environment. Shurin et al. (4) review how nerves, especially glial Schwann cells, can create tumor-friendly inflammatory Copyright Ó2020 by The American Association of Immunologists, Inc. 0022-1767/20/$37.50 microenvironments and can serve as “magnets” to promote www.jimmunol.org/cgi/doi/10.4049/jimmunol.1990024 240 EDITORIAL tumor migration (metastasis). Once the tumor is formed and autoimmune encephalomyelitis, the classic mouse model of innervated, neurons can generate immunosuppressive cytokine multiple sclerosis. The author describes the Th1/Th17 nature milieus and have a profound negative impact on therapeutic of experimental autoimmune encephalomyelitis and the responses. soluble factors that drive inflammatory responses, resulting The collection then shifts focus to the CNS, historically in myelin destruction. Karpus also discusses the opportu- thought to be devoid of lymphoid cells under healthy con- nities and challenges of targeting these cytokine culprits ditions due to their exclusion by the blood–brain barrier. with a new generation of therapeutics. Pierce and colleagues Recent breakthrough studies, however, indicate that immune (11) conclude with an update on the quest to understand cells do reside within the CNS, especially in the meninges cerebral malaria, a disease characterized by uncontrolled surrounding the parenchyma, and that special mechanisms immune responses to Plasmodium infections that can result are at play to enforce “immune privilege.” Kipnis and col- in long-term disabilities, especially in children. The authors leagues (5) review the current understanding of CNS immune describe exciting advances in a mouse model for cerebral structures and how cerebral spinal fluid likely serves as a malaria, and how this model will be employed in a search highway for the movement of CNS-derived Ags toward for therapeutic interventions. meningeal immune cells and into the peripheral immune Together, this collection will provide readers with a panoramic system. Although our current understanding of these ana- overview of leading-edge research on the complex conversations tomical connections is inchoate, progress in this area will have that transpire continuously between the nervous and immune broad implications for infectious disease, autoimmunity, and systems. Although the field of neuroimmunology has advanced Downloaded from immune responses to CNS tumors. in leaps and bounds, much work yet remains. New insights One of the sole immune cell types to reside in the pa- are especially imperative given the advancing age of our human renchyma is the microglia, a CNS-resident macrophage. In population, which will only escalate the prevalence of neuro- aselectedPillars of Immunology article and accompanying degenerative disorders with immune/inflammatory origins. Once commentary, Antel et al. (6) describe their pioneering again, immunologists will play a vital role this quest, as we work in culturing adult human microglia from healthy expand and strengthen our collaborative networks to include http://www.jimmunol.org/ primary tissues. This advance permitted the first charac- neuroscientists and neurologists. Only then will we understand terizations of microglial signatures at the molecular level how to control the neuroimmune dialogue, confining it to its and furthered the understanding of how microglia con- primary role: to sense and protect us from the harsh world in tribute to immune responses, clear debris, and communi- which we live. cate with astrocytes,