SCIENCE sciencemag.org

By Henrique Veiga-Fernandes1 and

David Artis2

Maintenance of mammalian tissue

homeostasis and function requires

coordinated actions of multiple cel-

lular and molecular networks. This

complexity is reflected in the im-

mune system, which is composed of

a plethora of cells that constitute the innate

and adaptive immune system and which

can sense multiple endogenous and exog-

enous factors. Similarly, the nervous system

includes a myriad of distinct neurons that

perceive, integrate, and respond to ever-

changing environmental conditions. Func-

tional interactions between the neuronal

and immune systems have been reported in

health and disease, such as in multiple scle-

rosis, autism, cancer, and chronic inflamma-

tory disorders (1). More recently, a number

of studies have revealed that discrete neu-

ronal and immune cells share anatomical

localization and interact functionally, form-

ing neuroimmune cell units (NICUs) that

orchestrate tissue homeostasis and integrity

(2). These findings are provoking a funda-

mental paradigm shift in our understanding

of neuronal–immune cell interactions. A re-

cent noteworthy example is the finding that

the nervous system can have a major regula-

tory effect on multiple innate immune cells

with functional impact in several physiologi-

cal processes (3–8).

Earlier studies established that signals

from the parasympathetic vagus nerve,

which connects the brainstem with periph-

eral organs, can have an anti-inflammatory

effect via tuning the activity of macrophages,

innate immune cells that engulf pathogens

and cell debris, leading to the production

of macrophage-derived immunomodula-

tory molecules (9). Bidirectional neuronal-

macrophage interactions were also shown

to regulate important aspects of intestinal

physiology. Notably, intestinal macrophages

control myenteric neuron activity and small

intestine peristalsis (muscular contractions

that move food down the intestine) in re-

sponse to microbial signals in the intestines

(3), whereas intestinal pathogenic bacterial

infections activate neurons to produce nor-

epinephrine that induces a tissue-protective

program in enteric macrophages (4). Nota-

bly, neuron-associated macrophages are also

present in adipose tissue and were shown

to buffer sympathetic neuronal activity and

fat tissue physiology, thus controlling obe-

sity and organismal metabolism (10). Den-

dritic cells and mast cells (both components

of the innate immune system) also interact

with peripheral neurons (1). For example,

upon chemical irritation or infection with

fungi, sensory neurons in the skin instruct

dermal dendritic cells to produce the cyto-

kine interleukin-23 (IL-23), which activates

adaptive T lymphocytes to produce pro-

inflammatory cytokines (11). Reciprocally,

lymphocyte-derived type 2 cytokines—such

as IL-4, IL-5, and IL-13—were also shown to

induce chronic itch via sensory neuron ac-

tivation (12). Together, these findings dem-

onstrate that neurons can trigger functional

molecular cascades that lead to the activa-

tion of innate and adaptive immune cells,

influencing immunity to infection, chronic

inflammation, and restoration of tissue ho-

meostasis. Nevertheless, defining additional

pathways that operate in the opposing direc-

tion, whereby immune cells can modulate

neuronal activity, requires further study.

But how widespread and biologically im-

portant is this neuronal-immune interaction?

Over the past decade, we have witnessed the

formal discovery of innate lymphoid cells

(ILCs) and their roles in development, infec-

tion, inflammation, metabolic disease, and

cancer (13). ILCs are a relatively rare cell

type, but they are particularly abundant at

barrier surfaces that are exposed to the ex-

ternal environment, which are also densely

populated with neuronal cells. Group 2 ILCs

(ILC2s) are associated with allergy and para-

sitic worm infections and were reported to

respond to vasoactive intestinal peptide

signals that were presumably derived from

neuronal cells (14), suggesting that neuronal-

The authors also speculate that SdrG may

bind its ligand through a catch bond—that

is, a bond strengthened by tensile force, as

observed with the Escherichia coli adhesin

FimH (10). Supporting this idea, a recent

single-molecule study demonstrated that

the mechanical strength of ClfB increases

dramatically as mechanical force is ap-

plied (11). The results suggested that ClfB-

mediated adhesion is enhanced through

force-induced conformational changes in

the adhesin, which changes from a weakly

binding folded state to a strongly bind-

ing extended state. This force-dependent

ligand-binding mechanism may help S. au-

reus to attach firmly to biomaterials under

high shear stress, and to detach under low

shear stress to colonize new sites.

The study by Milles et al. has important

implications for many fields. In molecular

microbiology, the combined use of AFM

experiments and SMD simulations should

greatly contribute to the identification of

new binding mechanisms in bacterial ad-

hesins, thus helping to show how they reg-

ulate biofilm formation. In diagnosis and

therapy, this combined approach could

represent a powerful platform for the treat-

ment of microbial infections. For instance,

correlative single-molecule experiments

and simulations could be used to screen

antiadhesion compounds for their poten-

tial to prevent or treat biofilm-associated

infections (12). The binding mechanism

reported here may also serve as a basis for

the development of bioinspired glues that

stick under water and outperform tradi-

tional adhesives. j

REFERENCES

1. J. W. Costerton, P. S. Stewart, E. P. Greenberg, Science 284, 1318 (1999).

2. L. F. Milles, K. Schulten, H. E. Gaub, R. C. Bernardi, Science 359, 1527 (2018).

3. T. J. Foster, J. A. Geoghegan, V. K. Ganesh, M. Höök, Nat. Rev. Microbiol. 12, 49 (2014).

4. K. C. Neuman, A. Nagy, Nat. Methods 5, 491 (2008). 5. J. Xiao, Y. F. Dufrêne, Nat. Microbiol. 1, 16186 (2016). 6. K. Ponnuraj et al., Cell 115, 217 (2003). 7. P. Herman et al., Mol. Microbiol. 93, 356 (2014). 8. M. Grandbois, M. Beyer, M. Rief, H. Clausen-Schaumann,

H. E. Gaub, Science 283, 1727 (1999). 9. A. Persat et al., Cell 161, 988 (2015). 10. E. V. Sokurenko, V. Vogel, W. E. Thomas, Cell Host Microbe 4,

314 (2008). 11. P. Vitry et al., mBio 8, e01748 (2017). 12. C. Feuillie et al., Proc. Natl. Acad. Sci. U.S.A. 114, 3738 (2017).

10.1126/science.aat3764

NEUROIMMUNOLOGY

Neuronal–immune system cross-talk in homeostasisInteractions between immune and neuronal cells are pillars in tissue homeostasis

1Champalimaud Research, Champalimaud Centre for the Unknown, 1400-038 Lisboa, Portugal. 2Jill Roberts Institute for Research in Inflammatory Bowel Disease, Joan and Sanford I. Weill Department of Medicine, Department of Microbiology and Immunology, Weill Cornell Medicine, Cornell University, New York, NY 10021, USA. Email: henrique.veigafernandes@research.fchampalimaud.org; dartis@med.cornell.edu

“The extreme mechanical stability of SdrG explains… how staphylococci colonize biomaterials so efficiently…”

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ILC interactions could also occur at mucosal

barriers. Consistent with this concept, group

3 ILCs (ILC3s) were shown to control intesti-

nal health as part of a glial cell–ILC3 unit or-

chestrated by neurotrophic factors (5). Glial

cells, considered to provide support and

protection to neurons, are adjacent to ILC3s

and integrate microbial-derived and host

alarmin (danger molecules that are released

upon tissue damage)–derived signals to con-

trol neurotrophic factor production (5). In

turn, these neuroregulatory molecules acti-

vate RET-expressing ILC3s that produce the

tissue-protective cytokine IL-22 (5). Thus,

glial cells translate microbial and host cues

into neurotrophic factor production, which

target coordinated neuronal and ILC3 func-

tions to promote intestinal tissue repair af-

ter exposure to infectious and inflammatory

stimuli (see the figure).

Adding to the growing understanding of

NICUs, other recent studies revealed that

mucosal neurons regulate the production

of ILC-derived type 2 cytokines via the pro-

duction of the neuropeptide neuromedin

U (NMU) (6–8). NMU-producing choliner-

gic neurons are adjacent to intestinal and

pulmonary ILC2s, whereas NMU receptor 1

(NMUR1) is selectively expressed by ILC2s

(6–8). Notably, activation of ILC2s with this

neuropeptide leads to a rapid and potent

production of type 2 inflammatory and

tissue-protective cytokines (6, 7). Consistent

with this, activation of this signaling axis

in ILC2s in vivo leads to rapid type 2 cy-

tokine responses after exposure to parasite

infections or allergens (6–8). The capacity

of neuronal-derived signals to rapidly trig-

ger ILC2 responses may also explain in part

why, despite their relatively low numbers,

ILC2s can be rapidly activated and have pro-

found effects across large barrier surfaces.

In addition to the activating func-

tions of cholinergic nerve–derived NMU,

catecholaminergic neurons—a component

of the sympathetic nervous system that is

a potent source of molecules such as nor-

epinephrine that binds the b2-adrenergic

receptor (b2AR)—were shown to act as a

potent “off switch” that dampens ILC2 re-

sponses (15). b2AR deficiency resulted in

exaggerated ILC2 responses and type 2 in-

flammation in intestinal and lung tissues,

whereas b2AR agonist treatment, a frontline

therapy for asthma patients, was associated

with impaired ILC2 responses and reduced

inflammation in vivo (15). Together, these

new findings demonstrate that neuronal-

ILC units are poised to trigger immediate

barrier tissue protection programs through

a neuronal-immune “fast track” response

that can both switch on and switch off ILC2

responses, whereas activation by cytokines

and alarmins appears to follow a “regular

track,” inducing and sustaining ILC2 func-

tion with comparatively delayed kinetics.

How do neuronal cells sense environ-

mental perturbations to instruct immune

responses? Enteric neurons and glial cells

can sense microbial products, parasites,

and host alarmins through myeloid differ-

entiation primary response 88 (MYD88)

signaling in the neuronal cells to produce

ILC-activating neuroregulators (5, 6). Al-

though this local neuronal–innate immune

cell interaction is critical during pathogen

insults (5, 6), the nature of the efferent

nervous signals (impulses emerging from

the central nervous system) that may also

regulate peripheral immune cells remain

elusive. Nevertheless, perhaps local neural

networks function as relay stations of en-

vironmental stimuli, amplifying these local

insults through the increased expression of

neuroregulators that maximize rapid tissue-

protective responses of immune cells.

Understanding the broader roles of

NICUs in the regulation of tissue homeo-

stasis in the context of health and disease

is certainly a major challenge ahead. Nota-

bly, clarifying cellular and molecular play-

ers of NICUs could identify new putative

therapeutic targets in the context of chronic

inflammation, cancer, metabolic health,

and beyond. Because pathogens and other

environmental triggers have been major

drivers of mammalian evolution, connect-

ing immune and neuronal responses may

therefore be considered a paradigm of coor-

dinated multi-tissue physiology, suggesting

that throughout evolution, neuroimmune

networks may have also been selected at an

organismal level. The neuroimmune system

is out there to be explored. j

REFERENCES AND NOTES

1. H. Veiga-Fernandes et al., Cell 165, 801 (2016). 2. H. Veiga-Fernandes et al., Nat. Immunol. 18, 116 (2017). 3. P. A. Muller et al., Cell 158, 300 (2014). 4. I. Gabanyi et al., Cell 164, 378 (2016). 5. S. Ibiza et al., Nature 535, 440 (2016). 6. V. Cardoso et al., Nature 549, 277 (2017). 7. C. S. N. Klose et al., Nature 549, 282 (2017). 8. A. Wallrapp et al., Nature 549, 351 (2017). 9. M. Rosas-Ballina et al., Science 334, 98 (2011). 10. R. M. Pirzgalska et al., Nat. Med. 23, 1309 (2017). 11. L. Riol-Blanco et al., Nature 510, 157 (2014). 12. L. K. Oetjen et al., Cell 171, 217 (2017). 13. C. S. Klose, D. Artis, Nat. Immunol. 17, 765 (2016). 14. J. C. Nussbaum et al., Nature 502, 245 (2013). 15. S. Moriyama et al., Science 359, 1056 (2018).

ACKNOWLEDGMENTS

H.V.-F. is supported by the European Research Council, EU; Crohn’s and Colitis Foundation of America, USA; and Fundação para a Ciência e Tecnologia, Portugal. D.A. is supported by the U.S. National Institutes of Health (grants AI061570, AI087990, AI074878, AI083480, AI095466, AI095608, AI102942, and AI097333), the Burroughs Welcome Fund, and the Crohn’s & Colitis Foundation of America.

10.1126/science.aap9598

BMP2

CSF1 IL-22

GFL

NMU

NMUR1

IL-5

IL-13

MacrophagesMicrobiota signals induce macrophages to release

bone morphogenetic protein 2 (BMP2), leading to neurons secreting colony-stimulating factor 1 (CSF1), which makes macrophages grow.

Mucosal plexus

Circular muscle

Longitudinal muscle

Intestinal epithelium

Submucosa

Myenteric plexus

Extrinsic nerves

ILC2s

Allergy and parasitic worm infection lead to

cholinergic neuron production of NMU, which

activates ILC2s and leads to the production of

type 2 cytokines and tissue protection.

ILC3s

Bacterial and tissue damage activate glial cells to secrete GFL neurotrophic factors, which induce ILC3s to release the tissue- protective cytokine IL-22.

Glialcell

Cholinergic neuron

Macrophage

ILC2

ILC3

1466 30 MARCH 2018 • VOL 359 ISSUE 6383

Neuroimmune cell units (NICUs) at barrier surfacesNICUs modulate immune responses. For example, reciprocal neuron-macrophage and neuron-ILC interactions occur in the lungs (not shown) and intestines.

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