Partners and guardians of the nervous and immune systems
Authors: Catarina Sacristán
Journal: Trends in Immunology (2024)

'Adapt what is useful, reject what is useless, and add what is specifically your own'Bruce Lee We continue to marvel at the reciprocal interplay between the brain, our nervous systems (central and peripheral) and our immune system; each powerfully influencing the other to achieve homeostasis. For example, among our immune cells, microglia are great defenders, acting as brain caretakers, providing a desirable and useful environment, removing and cleaning what is not needed, but also functionally adapting to unique conditions for each individual. Unfortunately, the language between nervous and immune systems can also falter, contributing to a variety of diseases. These scenarios are at the forefront of countless research endeavors in the field of neuroimmunology where scientists work hard to decipher the many mysteries of such interconnected systems. In our May special issue (Neuroimmunology - I), we present a timely article collection that reflects recent advances in this discipline, offering pathways to unveil new research avenues. On this occasion, Trends in Immunology partnered with advisory board member Dr. Jony Kipnis from Washington University in St. Louis, to conceptualize some of the content of this issue. The articles in this issue specifically pertain to research in mammals, particularly rodents, combined with reports of human biology and disease. Evidently, we present only a fragment of the vast body of published research focusing on the significant crosstalk between the immune system and the central and peripheral nervous systems. You might notice an emphasis on microglia research in this issue, representing pervasive interest in the field, but not undermining other subfields that are equally important. Hence, because of space limitations, work from many other dedicated investigators could not be added, but please stay tuned for a second installment of a Neuroimmunology – II special issue, coming later in 2024. We begin our themed issue with five Spotlights showcasing recent, exciting work that our readers should be aware of. Michal Schwarz and colleagues discuss a report identifying arachnoid cuff exit points (ACEs) that anatomically connect the mouse/human arachnoid barrier in the brain and dura mater. These neuroimmune communication points are significant for brain waste drainage ( e. g., cerebral spinal fluid) and may be key in facilitating reverse immune cell influx and T cell priming in the brain during tissue injury; this has sparked interest in the therapeutic targeting potential of ACEs. In another article, Gommerman et al. comment on a study characterizing an epigenetically and metabolically controlled memory astrocyte subset that elicits proinflammatory responses to stimuli in the experimental autoimmune encephalomyelitis mouse model of multiple sclerosis, suggesting that these cells might drive sustained central nervous system (CNS) pathology. Accordingly, the concept of astrocytes (non-hematopoietic) modulating pathology has intriguing implications for human neurologic diseases and autoimmunity. In a third spotlight, Iwasaki and Baker reflect on new data demonstrating that in vivo type I interferon signaling impacts mouse microglia during early brain development, facilitating microglia clearance functions, and modulating sensorimotor behavior. This unexpectedly links antiviral immune activation, function, and animal behavior, where perturbations in the former could hypothetically contribute to disease states. In the Spotlight by Cyster and Kirthivasan, the authors highlight a study that characterizes dynamic dura-associated lymphoid aggregate structures capable of mediating humoral immunity in the mouse meninges during an immune response to viral infection. The work presents opportunities for mechanistically understanding the importance of such lymphoid structures in defense. In the final Spotlight, Stevens and colleagues discuss work that describes microglia at mouse fetal cortical boundaries during embryonic brain development, the similarity of these cells to postnatal, axon-tract -associated microglia, and their capacity to ameliorate damage due to tissue stress or injury. Collectively, these Spotlights include forward-looking deliberations and raise new important questions in the field. Jonathan Kipnis and colleagues, in an Opinion, draw an analogy comparing the efforts made by immune cells to battle neurodegeneration in the CNS to those of a construction and repair crew, both of which can create chaos and havoc. Accordingly, they suggest that cellular immunotherapies might be tested and used to restore the diseased brain by boosting the immune system and disabling an inadvertent contribution to neurodegeneration. Lukens and Zengeler propose in their Opinion commentary, that microglia can be seen as harboring a molecular toolkit that endows them with powerful protective abilities; however, this toolkit needs to be carefully calibrated to curtail harmful off-target effects. The authors argue that to treat certain neurological disorders and modulate microglial functions, we must reach an in-depth mechanistic understanding of the different receptors, downstream signaling pathways, and the resulting outcomes. Ferreira Da Mesquita and Rua discuss the roles of CNS non-parenchymal border associated macrophages (BAMs), which are vital in controlling tissue homeostasis during aging and infections, and in response to Alzheimer's disease-like pathology. In this Opinion, they hypothesize that multiple infections can elicit the deterioration of BAMs, inducing pathogenesis and triggering cognitive decline with aging. A Review by Molofsky and Escoubas offers compelling and up-to-date information about microglia functions. The authors suggest that these guardian cells, in addition to being regulated by cytokine cues, are controlled by the sensing of brain-associated molecular patterns, which help translate information about neuronal activity and neural circuit remodeling. From a different angle, other articles focus on the connection between the peripheral nervous system and the immune system. Sokol and coworkers discuss in their compelling Review how skin-innervating sensory neurons can detect harmful signals, including pathogens, allergens, tissue-derived alarmins, and immune-derived cytokines. By releasing neuropeptides, these neurons provide the necessary neuroimmune interactions to activate innate and adaptive immunity at the skin barrier. Along these lines, de Pinho-Ribeiro and colleagues describe in their informative Review, mechanisms and pathways by which sensory neurons can influence immune responses to viruses, bacteria, helminths, and cancer cells. These findings and insights have important implications for the development of putative therapeutic interventions in immune-related diseases. We hope that you enjoy this themed collection of exciting updates, provocative opinions, and comprehensive views on some of the current and emerging paradigms of this interdisciplinary field. Absorb, reject, and conceptually adapt. Feel free to send comments to [email protected] or @TrendsImmuno and keep reading!