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Immune Cells Exploit a Neural Circuit to Enter the CNS

Kevin J. Tracey1,* 1Laboratory of Biomedical Science, Feinstein Institute for Medical Research, 350 Community Drive, Manhasset, NY 11030, USA *Correspondence: [email protected] DOI 10.1016/j.cell.2012.01.025

Multiple sclerosis (MS) is associated with the appearance of autoreactive T cells in the central nervous system. Using a mouse model of MS, Arima et al. now show that this attack begins at a specific spinal cord location. T cell entry into the CNS is regulated by a reflex neural circuit originating from leg muscle contractions.

On October 8, 1958, Dr. Ake Senning of cholinergic neurons traveling with the va- cally referred to as ‘‘sympathetic’’), it the Karolinska Institute in Stockholm, gus nerve to the heart (also reducing heart is neither sympathetic nor parasympa- Sweden surgically placed the first im- rate), thus maintaining blood pressure thetic. Displaying remarkable prescience, plantable cardiac pacemaker in a 43- within a narrow homeostatic range. These Henry Dale, who first isolated acetylcho- year-old man. Previously disabled by a long-established principles of reflex con- line in the spleen, famously cautioned potentially lethal cardiac arrhythmia syn- trol of organ homeostasis are well known against such terminology in his 1936 drome, the patient went on to live a long and have been widely explored in rela- Nobel Prize lecture, describing it as impre- life, to age 83, outlasting the surgeon. tively accessible organs of the gastro- cise. More accurate description of neural Since then, the medical, scientific, and intestinal, skeletal muscle, and neuro- circuits therefore requires terminology science fiction communities continue to endocrine systems. Less well known, based on the nature of the neurotransmit- be fascinated by the clinical implications however, is that recent advances over ters, not an inferred classification within of implanting medical devices that inter- the past decade in the field of neuro- the autonomic nervous system. face with the nervous system. Indeed, physiology have delineated similarly Now, Arima and colleagues report the device implantation is currently used for operating fundamental units of reflex neu- discovery of a specific neural circuit that clinical problems from broken hearts to ral action that regulate the immune modulates the acute activity of the adap- failing eyes. The prospect of using such system. tive rather than the innate immune sys- implants to precisely control the immune The inflammatory reflex is activated tem (Figure 1, right). Studying the mouse system, however, is now in the offing. In when increasing levels of inflammatory me- model of multiple sclerosis (MS) known this issue of Cell, Arima et al. (2012) diators from exogenous (e.g., pathogen- as experimental allergic encephalomy- present remarkable findings that advance associated molecular pattern [PAMPs]) elitis (EAE), in which CD4-positive T cells this possibility by showing that neural or endogenous (e.g., damage-associ- that have been primed to attack myelin- signals transmitted along adrenergic neu- ated molecular pattern [DAMPs]) mole- ated nerves are introduced into the rons regulate the influx of activated CD4- cules stimulate receptors in the vagus bloodstream, they noticed that, at the positive T cells into the central nervous nerve and associated glomus cells (Fig- earliest stages of disease progression, system during the onset of autoimmune ure 1, left) (Tracey, 2009). This leads to autoreactive T cells cross the blood- disease. afferent action potentials being trans- brain barrier at a highly specific location: To appreciate the full potential for mitted along the vagus nerve to the the fifth lumbar level of the spinal medical devices to control immune re- brainstem and other nuclei that control cord. Wondering why this specific point sponses, consider the example of phys- outgoing signals in the vagus nerve. In- acted as a gateway for T cells, they iological reflexes that control cardiac creased activity in the vagus to the spleen discovered that dorsal blood vessels ex- function. The baroreceptor reflex is acti- and other organs reduces the innate press high levels of the chemokine vated when increases in blood pressure immune system’s response to DAMPs CCL20. Reasoning that the fifth lumbar stimulate stretch receptors in the carotid and PAMPs, decreases the release of vertebrae lie close to the dorsal root sinuses and aortic arch, triggering action cytokines, and suppresses inflammation. ganglia of sensory neurons that innervate potentials that are transmitted along the Just as stimulating the vagus nerve can the soleus and other leg muscles, they vagus nerve to the brainstem and other slow heart rate, so too, increasing vagus decided to test whether silencing this nuclei that control outgoing pressor and nerve activity slows innate immunity. It is muscle-sensitive neuronal pathway would depressor responses. These include de- important to note here that, as the inflam- inhibit chemokine expression and patho- creased signaling in adrenergic nerves to matory reflex circuit utilizes both the vagus genic T cell entry. Incredibly, limiting the heart (reducing contractility and heart nerve (classically referred to as ‘‘parasym- contraction of the soleus muscle by simply rate) and increased signaling through pathetic’’) and the splenic nerve (classi- suspending the mice by their tail was

392 Cell 148, February 3, 2012 ª2012 Elsevier Inc. tors expressed on cytokine-producing macrophages in the marginal zone and red pulp. Cholinergic signaling sup- presses cytokine transcription and re- lease by downregulating the nuclear activity of NFkB. It is interesting to consider the thera- peutic implications of the present find- ings by Arima and colleagues of a reflex circuit that modulates blood-brain bar- rier integrity. It is now plausible that im- planted neurostimulating or inhibiting devices may be of therapeutic value for the treatment of neurological autoimmune disease. Knowledge of the inflammatory reflex spawned research into experi- mental pacemaker-like devices to stimu- late the vagus nerve. These have already been shown to confer significant protec- tion against other inflammatory disease syndromes, such as in animal models of adjuvant arthritis, inflammatory bowel disease, ischemia-reperfusion, and sep- sis (Koopman et al., 2011). Pharmaco- logical agents that target this pathway using selective agonists of a7 nAChR confer significant protection against diet-induced obesity, acute lung injury, asthma, insulitis, insulin resistance, and atherogenesis. The molecular mechanism underlying the inflammatory circuit requires signal Figure 1. Neural Reflex Circuits Control Function of the Immune System transduction via the a7 nAChR. The As described in the text, the inflammatory reflex and the ‘‘gateway reflex’’ modulate the innate and adaptive immune responses to threat. electrical signals generated by the device are relayed by neuronal signaling to the target organ and are converted there sufficient to reduce CCL20 expression to understand the specific cell receptor into cholinergic signals that can be also and block accumulation of T cells at the targets. be recapitulated by administration of gateway. Understanding of the inflammatory highly selective a7 nAChR agonists to Their findings raise the possibility that reflex recently took on a new twist, with block inflammation. Thus, whereas these a reflex circuit controls a critical step in the findings that the circuitry that culmi- devices are computerized impulse gener- the progression of autoimmune disease. nates on cytokine-producing macro- ators that create electrical signals in The precise route by which skeletal phages in the spleen not only requires specific nerves, the nature of the inflam- muscle activity influences the vascular three neurons and two neurotransmitters, matory reflex as a neural circuit converts endothelium is not yet clear but may in- but also involves an unusual role for the electrical signal back to the pharma- volve three neurons: the sensory neuron, T cells (Figure 1, left). The first neuron in cological. Many epidemiologically im- traveling up to the brain stem; efferent the reflex is sensory, traveling in the vagus portant diseases, including those listed cholinergic neurons descending in the nerve to the brain stem. The second is above, occur because inflammation fails sympathetic chain from the brainstem; cholinergic and travels in the vagus nerve to resolve (Nathan and Ding, 2010). Wide- and the adrenergic neurons that innervate to the celiac ganglion. The third neuron, spread clinical evidence reveals that a the endothelial cell. A similar muscle which arises there, is adrenergic and failure of vagus nerve signaling can con- to adrenergic neuron arrangement has travels in the splenic nerve to deliver nor- tribute to this resolution failure. Vagus been implicated in the exercise pressor epinephrine to b2 adrenergic receptors nerve activity is decreased in patients reflex, a three-neuron circuit that modu- expressed on a subset of T cells capable with autoimmune and autoinflammatory lates the cardiovascular response to exer- of secreting acetylcholine (Rosas-Ballina diseases, and it is quite plausible that cise. It will be extremely important to et al., 2011). Remarkably, T cells therefore the absence of tonic inhibitory signals in follow the advances in further defining act in place of cholinergic neurons, acti- the inflammatory reflex facilitates the non- this neural circuitry, a ‘‘gateway reflex,’’ vating a7 nicotinic acetylcholine recep- resolution of inflammation.

Cell 148, February 3, 2012 ª2012 Elsevier Inc. 393 Whereas the reflex principles described ACKNOWLEDGMENTS Koopman, F.A., Stoof, S.P., Straub, R.H., Van here are prototypical and well under- Maanen, M.A., Vervoordeldonk, M.J., and Tak, 17 stood, it is quite likely that additional, as Kevin Tracey is a cofounder of Setpoint Medical. P.P. (2011). Mol. Med. , 937–948. yet undiscovered neurophysiological re- Nathan, C., and Ding, A. (2010). Cell 140, 871–882. flexes will be mapped. The findings of Rosas-Ballina, M., Olofsson, P.S., Ochani, M., REFERENCES Arima and colleagues represent a signifi- Valde´ s-Ferrer, S.I., Levine, Y.A., Reardon, C., cant advance in this field and are likely Tusche, M.W., Pavlov, V.A., Andersson, U., Cha- Arima, Y., Harada, M., Kamimura, D., Park, J.-H., van, S., et al. (2011). Science 334, 98–101. to expand interest in new mechanisms Kawano, F., Yull, F.E., Kawamoto, T., Iwakura, Y., and therapeutic strategies to specifically Betz, U.A., Ma´ rquez, G., et al. (2012). Cell 148, Tracey, K.J. (2009). Nat. Rev. Immunol. 9, modulate the activity of neural circuits. this issue, 447–457. 418–428.

A New Histone at the Centromere?

Daniel R. Foltz1 and P. Todd Stukenberg1,* 1Department of Biochemistry and Molecular Genetics, University of Virginia, School of Medicine, Charlottesville, VA 22908, USA *Correspondence: [email protected] DOI 10.1016/j.cell.2012.01.023

The centromere is a classic system to study epigenetic specification, and most research has focused on a specialized histone variant, CENP-A, that is required for kinetochore assembly. Now Nishino et al. reveal a new level of complexity for centromeric chromatin, by showing that the kinetochore complex CENP-T-W-S-X shares structural and functional properties with canonical histones.

The centromere is a unique domain of and how centromeres are epigenetically meres. To highlight this exciting hypoth- chromatin that is present as a single, propagated. The structures also provide esis, we will review the similarities and stable locus on each chromosome. The an exciting look into the atomic structure differences of CENP-T-W-S-X and a best known function for centromeres is of the constitutive centromere. canonical nucleosome. to assemble the mitotic kinetochore, Canonical nucleosomes contain four In both histones and non-DNA-binding a protein complex required for proper types of histones: H2A H2B, H3, and H4. proteins, two histone folds associate segregation of chromosomes. A central Four CCAN proteins, CENP-T, CENP-W, with each other to form a heterologous feature of all eukaryotic centromeres is CENP-S, and CENP-X, are predicted to dimer. In histones, two of these dimers a specialized nucleosome containing the have histone folds, suggesting that a then come together to form tetramers CENP-A protein. Centromeres contain new histone might form at the centro- (Figure 1A). Nishino et al. confirm the 16 other proteins, called the constitutive mere. However, histone folds are also formation of the CENP-T-W and CENP- centromere-associated network (CCAN), found in non-nucleosomal proteins, such S-X subcomplexes by in vitro reconstitu- which are recruited to the centromere by as the transcription factor proteins NF- tion (Amano et al., 2009; Hori et al., 2008). CENP-A nucleosomes. Until now, little YB/C, NC2a-b, and components of the They then solve the crystal structures structural data were available to explain TAF complex. In these non-nucleosomal of each subcomplex. These structures how the constitutive centromere func- contexts, the histone folds can act as demonstrate that CENP-T-W and CENP- tions. In this issue, Nishino et al. (2012) heterologous dimerization domains, as is S-X dimerize through their histone-fold perform a detailed structural analysis of the case for the TAF proteins, and also domains. They combine the two subcom- four CCAN proteins: CENP-T, CENP-W, as DNA recognition motifs, as is the plexes to form the T-W-S-X heterote- CENP-S, and CENP-X (CENP-T-W-S-X). case for the NF-YB/C proteins. In con- tramer, which contains a single copy of The authors show that CENP-T-W-S-X trast, the data presented by Nishino each protein. The interface between the forms a heterotetrameric complex et al. suggest that the CENP-T-W-S-X CENP-T-W and -S-X heterodimers occurs capable of binding and wrapping centro- complex shares both structure and func- in regions of CENP-T and CENP-S, which meric DNA. This observation has signifi- tional properties of a canonical histone, are similar to that observed in histone cant implications for how kinetochores suggesting that CENP-T-W-S-X could heterotetramers. An important difference are anchored to centromeric chromatin form a new type of nucleosome at centro- between these complexes is that the

394 Cell 148, February 3, 2012 ª2012 Elsevier Inc.