Published Online: 16 January, 2018 | Supp Info: http://doi.org/10.1084/jem.20172295 Downloaded from jem.rupress.org on August 6, 2018
Department of Neuroscience, Center for Brain Immunology and Glia (BIG), School of Medicine, University of Virginia, Charlottesville, VA
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The brain is our computing machine that integrates stimuli from the environment and orchestrates responses to these stimuli. Here, I propose that the de ning role of the immune system is to sense microorganisms and to inform the brain about them.
This is a tale of two systems. Both the central nervous system and the immune system are composed of heterogeneous cell populations. Both encompass enor- mous variability and heterogeneity within each cell type. Both release and respond to neurotransmitters and cyto- kines. Both sense environmental stimuli. Both respond to deviations in homeo- stasis. Both use “synapses” for cell–cell interactions. Both generate and store memories. The two systems were be- lieved to live separately from each other to ensure a person’s health. Interaction between them, when it occurred, was considered for decades as pathological. Recent works from numerous laborato- ries suggest that the time has come for reappraisal of these assumptions.
Why would nature disconnect two such vital systems from one another? We have evolved as multicellular organisms within an ocean of microorganisms. Pre- sumably, the evolution of our immune system is what has allowed us to prevail. Our brain is a computing center, a su- percomputer that constantly surveys our external and internal environments and responds to the plethora of cues they present (Fig. 1). We have ve senses— visual, olfactory, gustatory, somatosen- sory, and auditory. In addition, the vagus nerve delivers information about our visceral organs to the brain, referred to by some as the sixth sense (Zagon, 2001; proprioception, a sense of position and movement, is also often referred to as the sixth sense; Smith, 2011). Senses are needed to report to the brain about the external (and internal) environment for
Correspondence to Jonathan Kipnis: firstname.lastname@example.org
it to compute activity to preserve the organism. But how does our supercom- puter “sense” (and protect us from, when needed) the microorganisms that live within us (the commensals), surround us, or antagonistically invade us? Is it conceivable that the brain would give up on the ability to sense the world of microorganisms in which we survive?
I would like to propose that the de ning role of the immune system is to sense the microorganisms and to deliver the necessary information about them to the brain. The immune response, therefore, should be hardwired in our brain, which makes the immune system our “seventh sense” (Fig. 1).
There are several examples of im- mune inputs a ecting neural circuits.We have recently shown that IFN-γ, by di- rectly a ecting the inhibitory neuronal layers I/II, regulates circuits underlying social behavior (Filiano et al., 2016). IL-17 has been implemented in sen- sory function (Chen et al., 2017) and in social behavior (Shin Yim et al., 2017). The role of TNF and IL-1 in a ecting neural circuits was demonstrated years ago (Stellwagen and Malenka, 2006; Prieto et al., 2015). This is just a partial list of immune signaling molecules af- fecting neuronal function.
Holding a conversation in a noisy place or with impaired hearing is di – cult. Food tastes di erent when we can- not smell it or feel its texture.The brain receives such sensations as stimuli and computes its responses, but all relevant circuits are interconnected so that inter- ference with one alters the function of
others (and of the brain as a unit). Some circuits have more interconnections than others, and thus the impact of their disturbance will be more widespread. When we are sick, for example, whether we are su ering from a minor cold or a more serious infectious illness, we feel weak and sleepy, and our appetite is de- pressed. Sickness in children usually af- fects their behavior, making them more inclined to be comforted by cuddling, whereas the e ect of a similar pathogen on adult patients may result in with- drawal behavior. Although the circuits modulating such behaviors are similar, the immune input (immune neuromod- ulation) in children and adults may di er su ciently to change their behavioral manifestations from one extreme to the other, yet in all cases molecules derived from immune cells are implicated as potential modulators of brain function. Sickness behavior could thus be viewed, for example, as an overwhelming input into the brain via the seventh sense, re- sulting in interference with other cir- cuits that receive the inputs. Similarly, an impaired or dysfunctional immune system could lead to abnormal conse- quences. Failure to properly sense the pertinent microorganisms (pathological, commensal, or both) might trigger an altered immune response, with adverse impact on brain function.
This uni ed theory of neuroim- mune interactions could explain why the elimination of certain types of im- mune cells alters behaviors (Kipnis et al., 2004; Ziv et al., 2006; Derecki et al., 2010) in ways that are similar to those
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J. Exp. Med. 2018 https://doi.org/10.1084/jem.20172295
The Journal of Experimental Medicine
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resulting from overactivation of the im- mune system (Dantzer and Kelley, 2007; Godbout et al., 2008; Moreau et al., 2008; Fu et al., 2010). It could also ex- plain why microglia, the only parenchy- mal resident immune cells, are associated with many (if not all) neurodegenerative conditions (Prinz et al., 2017). Spillover of the immune signals aimed at neurons may be received by microglia. Microglia may respond to these signals and impact neural function or simply be an acti- vated bystander that indicates an abnor- mal immune input but does not impact the progression of the disease.
The suggestions above are enig- matic because we have yet to recapitulate the neuroimmune connectome—a de- tailed map of connections, interactions, and interdependencies between di erent immune cell–derived molecules (mostly cytokines) and neural circuits. Once the connectome emerges through empirical (single-cell sequencing) and theoretical/ mathematical modeling (clustering of cy- tokine receptors that may predict circuits most susceptible to particular immune
inputs) approaches, it can be expected to yield a better understanding of the an- atomical and functional organization of the seventh sense and its targeted circuits. By recognizing and unraveling the phe- nomenon of the neuro–immune axis as a structural code of the brain, we will get closer to understanding the essence—eti- ology,course,andpotentialtherapies—of many neurological diseases.
I would like to thank S. Smith for editing the manuscript and Anita Impagliazzo for the art work. I also thank all the members of my lab for their valuable comments during multiple discussions of ideas presented here.
This work was supported by grants from the Na- tional Institutes of Health (AG034113, AG057496, and NS096967).
The author declares no competing nancial interests.
Chen, C., et al. 2017. Nature. https://doi.org/10 .1038/nature20818
Dantzer, R., and K.W. Kelley. 2007. Brain Behav. Immun. https://doi.org/10.1016/j.bbi.2006.09 .006
Derecki, N.C., et al. 2010. J. Exp. Med. https://doi .org/10.1084/jem.20091419
Filiano, A.J., et al. 2016. Nature. https://doi.org/10 .1038/nature18626
Fu, X., et al. 2010. J. Neuroin ammation. https://doi .org/10.1186/1742-2094-7-43
Godbout, J.P., et al. 2008. Neuropsychopharmacology. https://doi.org/10.1038/sj.npp.1301649
Kipnis, J., et al. 2004. Proc. Natl. Acad. Sci. USA. https://doi.org/10.1073/pnas.0402268101
Moreau, M., et al. 2008. Brain Behav. Immun. https ://doi.org/10.1016/j.bbi.2008.04.001
Prieto, G.A., et al. 2015. Proc. Natl.Acad. Sci. USA. https://doi.org/10.1073/pnas.1514486112
Prinz, M., et al. 2017. Nat. Immunol. https://doi .org/10.1038/ni.3703
ShinYim,Y., et al. 2017. Nature. https://doi.org/10 .1038/nature23909
Smith, R. 2011. Gesnerus.
Stellwagen, D., and R.C. Malenka. 2006. Nature.
Zagon, A. 2001. Trends Neurosci. https://doi.org /10.1016/S0166-2236(00)01929-9
Ziv, Y., et al. 2006. Nat. Neurosci. https://doi.org /10.1038/nn1629
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Immune system: The “seventh sense” | Kipnis
Figure 1. A schematic representation of the senses that are hardwired in the brain. The senses that protect the individual from external and in- ternal perturbations through a contact delivery of information to the brain include the ve senses, the proprioception, and the seventh sense—immune input. The peripheral immune cells detect microorganisms and deliver the information to the brain. Although neurons are the primary targets, when an excess of immune information is delivered (in pathology), microglia respond either as bystanders or as active players. (Note that arrows schematically indicate inputs of senses into the brain circuits but not the precise position of where each sense is being projected.)