From head to tail it’s a 2 way street for neuro-immune communication

A Anderson and R McMullan

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From head to tail it’s a 2 way street for neuro-immune communicationA Anderson and R McMullan

From head to tail it’s a 2 way street for neuro-immune communication

A Anderson and RQ1 McMullan*Department of Life Sciences; Imperial College London; South Kensington Campus; London, UK

Animals need to be able to rapidly and5 effectively respond to changes in

their external and internal environment.To achieve this the nervous and immunesystems need to coordinate theirresponses, integrating multiple cues

10 including presence of potential patho-gens, and availability of food. In ourrecent study 1 we demonstrate that sig-naling by sensory neurons in the headusing the classical neurotransmitter sero-

15 tonin can negatively regulate the rectalepithelial immune response upon infec-tion of C. elegans with the naturallyoccurring bacterial pathogen Microbacte-rium nematophilum (M. nematophi-

20 lum). The complicated nature of themammalian brain and immune systemhas made it difficult to identify themolecular mechanisms mediating theseinteractions. With its simple, well

25 described, nervous system and a rapidlygrowing understanding of its immunesystem, C. elegans has emerged as anexcellent model to study the mechanismsby which animals recognize pathogens

30 and coordinate behavioral and cellularimmune responses to infection.

Chemosensory NeuronalSignaling Acts Upstream ofEpithelial Immune Responses

35 C. elegans commonly encounters manyenvironmental hazards including patho-genic bacteria. In order to respond appro-priately, the worm must integratemultiple environmental cues including

40 food availability and pathogenicity tomaximize its chances of survival. What arethe molecular mechanisms that allow thisfinely tuned integration of informationfrom both the nervous and immune sys-

45 tems? Previous work has shown that

neuronal signaling can profoundly affectsusceptibility to infection by mediatingpathogen avoidance.2,3 Mutations in theneuronally expressed G protein coupledreceptor (GPCR) npr-1 gene, which enco-des a homolog of the neuropeptide Yreceptor, can mediate the behavioralimmune response of avoidance of a num-ber of pathogens including Pseudomonasaeruginosa.3 In comparison, our recentwork has shown that during M. nemato-philum infection, signaling via the neuro-transmitter serotonin can suppress thecellular immune response in the rectal epi-thelium (Fig. 1A).1

How does neuronal signaling influencethe immune response? The amphid che-mosensory neuron pair ADF, which areexposed to the external environment, havethe ability to modulate behavioral andcellular immune responses to Pseudomo-nas aeruginosa and M. nematophilum.1,2

These responses rely on the regulation ofthe biosynthetic enzyme tryptophanhydroxylase-1 (tph-1) in ADF neurons.TPH-1 is the rate-limiting enzyme in thesynthesis of serotonin, and animals carry-ing a putative null allele for this gene aredeficient for serotonin production and sig-naling.4 Transcription of tph-1 in ADF isregulated by a number of conditionsincluding food quality, availability andheat stress.2,5,7 Our work shows that thecellular immune response to M. nemato-philum is negatively regulated by tph-1expression in ADF neurons and that thisacts via the serotonin receptors SER-1 andSER-7 to regulate signaling by the G-pro-tein goa-1(Gao) in the rectal epithelium(Fig. 1A).1 M. nematophilum innatelyrepels C. elegans and this behavioralimmune response is not affected by muta-tions in tph-1.1,8 Using a transcriptionalreporter we found that exposure to thispathogen does not increase tph-1

Keywords: G proteins, immune response,infection, sensory neurons, serotonin

Abbreviations: C. elegans, Caenorhabditiselegans; M. nematophilum, Microbacte-rium nematophilum; GPCR, G-protein-coupled receptor; CaMKII, Calcium/cal-modulin-dependent protein kinase II;DCV, Dense Core Vesicle; NK cell, Natu-ral Killer cell; tph-1, tryptophan hydroxy-lase-1

*Correspondence to: R McMullan; Email: r.mcmullan@imperial.ac.ukQ2

Submitted: 05/07/2014

Revised: 06/03/2014

Accepted: 06/25/2014

http://dx.doi.org/10.4161/21624046.2014.959425

Commentary on; Serotonergic ChemosensoryNeurons Modify the C. elegans ImmuneResponse by Regulating G-Protein Signaling inEpithelial Cells.

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Worm 0:0, e959425; September 1, 2014; © 2014 Taylor & Francis Group, LLCCOMMENTARY

expression in ADF.1 In comparison, inresponse to contact with the pathogenPseudomonas aeruginosa, C. elegansundergoes a behavioral immune response,

95 learning within hours to avoid the smell

of Pseudomonas. In this case, Pseudomo-nas ingestion increases intracellular cal-cium, which then increases tph-1transcription and the levels of serotonin inADF.9 This response is cell-autonomously

regulated by the C. elegans homolog ofcalcium/calmodulin-dependent proteinkinase II (CaMKII), UNC-43.9 This sug-gests that the same gene in the same che-mosensory neurons can show differential

Figure 1. Neuronal signal-ing pathways that regulateC. elegans cellular immuneresponses. A number of mol-ecules released from DCVsact non-autonomously to reg-ulate the immune response.(A) Serotonin, synthesized byTPH-1, in ADF chemosensoryneurons acts via SER-1 andSER-7 receptors to suppressthe immune response to M.nematophilum infection.Serotonin acts, directly (i) orindirectly (ii), to regulateGOA-1 signaling in the rectalepithelium. Although SER-1and SER-7 receptors are notexpressed on rectal epithelialcells under standard condi-tions, it remains to be deter-mined whether regulation ofSER-1 and SER-7 expressionby infection may allow sero-tonin to act directly on thesecells (i). Alternatively seroto-nin may activate SER-1 andSER-7 expressed on neurons,which then release a signal toactivate GOA-1 signaling inrectal epithelial cells (ii). GOA-1 signaling acts upstream of,or in parallel to, EGL-30 sig-naling to suppress the Darphenotype and reduce path-ogen clearance rates.1 (B) Theoctopamine receptor, OCTR-1, suppresses the immuneresponse to infection withPseudomonas aeruginosaand is required in ASH andASI neurons to suppressPMK-1 signaling and theunfolded protein response innon-neuronal cells.15 (C)Release of INS-7 or DBL-1from the DCVs of unidentifiedneurons regulate geneexpression in the intestineand epithelial cells respec-tively to mediate antibacterialand antifungal resistance.13,14

In addition dopamine,released from DCVs protectsanimals from repeat infectionby enteropathogenic E.Coli.16

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regulation in response to different patho-gens, illustrating the precise and subtlelevels of control required.

210 Dense Core Vesicle Releaseand the Immune Response

Unlike small synaptic vesicles, whichare localized to synaptic zones, dense corevesicles (DCVs) are diffusely scattered

215 throughout the nerve terminal.10 DCVsrelease a number of bioactive moleculesincluding serotonin, and neuropepti-des,11,12 many of which influence theimmune response. Reducing DCV release

220 by mutations in unc-31 (the calcium acti-vator protein required for DCV secretion)results in increased resistance to Pseudo-monas aeruginosa infections, suggestingthat molecules released from DCV’s sup-

225 press this immune response.13 DifferentDCV cargoes are required to modulatethe response to different pathogen infec-tions. Our work has shown that exogenousserotonin suppresses the rectal epithelial

230 immune response to infection with M.nematophilum, while reductions in sero-tonin synthesis results in an increasedimmune response.1 In comparison, duringPseudomonas aeruginosa infections, loss

235 of serotonin has no effect on cellularimmunity, while mutations in the neuro-peptide processing enzymes egl-3 and egl-21 result in enhanced pathogen resis-tance.2,13 This is due to the action of the

240 insulin-like neuropeptide INS-7, acting asa DAF-2 agonist to negatively regulateresistance to Pseudomonas infection(Fig. 1C).13

Further DCV cargoes have also been245 implicated in modulating the immune

response. Zugasti et al. have demonstratedthat TGF-b signaling from the nervoussystem promotes expression of Caenacinpeptides in the epidermis following infec-

250 tion with the fungal pathogen Drechmariaconiospora (Fig. 1C).14 Recent work bythe Aballay lab has shown that duringPseudomonas infection OCTR-1, a puta-tive catecholamine receptor whose ligand

255 octopamine, is the invertebrate equivalentof noradrenaline, is required in ASH andASI neurons to negatively regulate thep38 MAPK and unfolded proteinresponse in pharyngeal and intestinal cells

(Fig. 1B).15 However, whether octop-amine acts as the OCTR-1 ligand tomediate this effect on the immuneresponse is currently unclear.15 Anothermonoamine neurotransmitter found inDCVs is dopamine. Although direct evi-dence that this neurotransmitter can mod-ulate the immune response is lacking,dopaminergic neurons have been shownto play a role in enabling the conditioningof C. elegans to enteropathogenic E. coliso that they are more resistant to infectionupon a second exposure (Fig. 1C).16

Although there is strong evidence thatmolecules released from DCVs modulatethe cellular immune response, the ques-tion of whether neurotransmitter releasefrom small synaptic vesicles can also affectinnate immune function remains to beaddressed. The availability of C. elegansmutants in enzymes required to synthesizethese neurotransmitters provides an excel-lent starting point to address this question.

Neuronal Signaling to ImmuneCells; A Direct or Indirect Action?

One key question is how signals origi-nating in neurons in the head are trans-mitted to distant targets such as the rectalepithelium or intestine. During M. nema-tophilum infection serotonin synthesizedand released from ADF chemosensoryneurons in the head acts via GOA-1 tomodulate the response of rectal epithelialcells in the tail. Although ADF forms syn-apses with 17 interneurons and sensoryneurons, as well as forming gap junctionswith 2 additional sensory neurons (www.wormweb.org), the rectal epithelium isnot reported to be a direct postsynaptictarget. Changes in neuronal connectivityin response to M. nematophilum infectionare possible, but our observations using atph-1 transcriptional reporter suggest thisnot the case (unpublished data). Serotonincan act at sites microns away from its siteof release to activate receptors,17 howeverwhether it is possible that it could traversethe length of the worm at a high enoughconcentration to activate receptors in therectal epithelium is unclear. An alternativeexplanation is that serotonin could medi-ate its actions on the rectal epitheliumindirectly. This is not a new concept,

indeed GOA-1 expressed on cholinergicmotor neurons in the ventral nerve cord isknown to act downstream of serotoninsignaling in the regulation oflocomotion.18

However, until recently it was notknown whether serotonin signaled directlyby binding to serotonin receptorsexpressed on these cholinergic neurons orindirectly by modulating the activity ofinterneurons, which subsequently activateGOA-1. Recent work by G€urel et al.revealed that the serotonin receptors con-trolling locomotion, MOD-1 and SER-4are not expressed in cholinergic motorneurons, but are expressed in non-overlap-ping sets of interneurons in the head andtail. MOD-1 is also expressed in GABAer-gic motor neurons in the ventral nervecord, suggesting that serotonin doesindeed act indirectly on GOA-1 in cholin-ergic motor neurons.19 Similarly, seroto-nin may act indirectly on GOA-1 tomodulate the immune response in the rec-tal epithelium. Our worked defined atleast SER-1 and SER-7 receptors as play-ing a role in modulating the epithelialimmune response.1 However, in theabsence of infection, the reported expres-sion for SER-1 and SER-7 places neitherreceptor in the rectal epithelium, suggest-ing that their action on the epithelium islikely to be indirect.

A Conserved Networkof G Proteins MediateNeurotransmission andEpithelial Immunity

Locomotion in C. elegans is dependentupon a network of G-proteins, includingEGL-30(Gaq) and GOA-1(Gao) whichact antagonistically in cholinergic motorneurons to regulate acetylcholine release.20

Loss of egl-30 results in reduced acetyl-choline release and locomotion. Animalslacking goa-1 show increased release andmovement, as well as being resistant to theenhanced slowing on food response medi-ated by serotonin, suggesting this responseis mediated by goa-1.18 Genetic data sug-gests that GOA-1 acts parallel to20 orupstream of 21 EGL-30 in locomotion. In2012, we showed that the immuneresponse to M. nematophilum in the

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rectal epithelium requires the EGL-30(Gaq)-UNC-73(TRIO)-RHO-1(RhoA)signaling pathway.22 Our most recentwork shows that GOA-1 signaling acts

370 antagonistically to this signaling pathwayin the rectal epithelium, acting upstreamof, or in parallel to, EGL-30.1 This dem-onstrates that the same conserved G-pro-teins can mediate different responses in

375 different tissues.

Neuro-Immune Signalingin Mammalian Systems

The concept of neuro-immune com-munication is not restricted to C. elegans.

380 Humans undergoing psychological stressshow changes in immune measures andare known to become more susceptible tonew infections or reactivation of a latentinfection.23,24 Clinical depression is asso-

385 ciated with changes in cellular immunity,including changes in lymphocyte prolifer-ation and natural killer (NK) cell activ-ity.25 In mammals both the innate andadaptive immune systems show interac-

390 tions with the nervous system. Mamma-lian immune cells express receptors forneurotransmitters, including serotonin,and can be influenced by neuronal signal-ing. Serotonin is released in response to

395 injury and pro-inflammatory signals26 andmany immune cells express receptors forserotonin including dendritic cells,27 mastcells28 and macrophages.29 Treating T-cells with exogenous serotonin can inhibit

400 proliferation and promote T-cell activa-tion.26 Serotonin can also act induce mastcell migration28 and proliferation of NKcells.30 Dopamine is also implicated inmediating immune responses in mam-

405 mals. Induction of dopamine release hasbeen shown to suppress systemic inflam-mation and improve survival in a mousemodel of sepsis.31

Evidence is also accumulating that this410 communication is bidirectional and that

the immune system can also modulateneuronal signaling. In response to infec-tion, mammalian immune cells can pro-duce neuropeptides, cytokines and

415 neurotransmitters that influence the ner-vous system and can lead to the develop-ment of sickness syndrome anddepression.32-34 This bidirectional

communication means that dysfunctionin the nervous system can have a signifi-cant impact on the immune system andvice versa. Indeed analysis of people withthe autoimmune condition rheumatoidarthritis reveals an increased incidence ofdepression.35

The role of the immune response inregulating neuronal function is yet to beexplored in C. elegans, however detailedcharacterization of the neuronal circuitsunderlying behavior, coupled with ourgrowing understanding of C. elegansimmunity, provides an excellent startingpoint for this work.

Future Perspectives

Our recent publication together withprevious data highlights the profoundinterrelationship between the nervous andimmune systems required for optimal sur-vival. Balancing the inputs of the 2 sys-tems is complex. For example, when foodis scarce expending resources mounting animmune response may not always be themost appropriate response. Likewise,mutants defective in DVC secretion arebetter at combating an opportunisticPseudomonas infection, but this is oftenaccompanied by defects in locomotionthat would likely prove detrimental to sur-vival in their natural environment. As clas-sical neurotransmitters become recognizedas immunomodulators, it will be interest-ing to determine whether synaptic vesiclerelease can also influence the immuneresponse or if this is restricted to DCVs.

Broadening our understanding of thedialog between the nervous and immunesystems has the opportunity to providenew treatments options for those develop-ing mood disorders post-infection, orreducing susceptibility to infection forthose experiencing psychological stress.The complexity of the mammalian ner-vous and immune systems mean that dis-secting out the signaling pathwaysimportant in integrating these systems isextremely difficult. This is why, since anear complete connectome for the nervoussystem of C. elegans exists, the simpleworm is likely to continue to play a signif-icant role in understanding the complex

interplay between the nervous andimmune systems in the future.

Funding

AA and RM are funded by a WellcomeTrust Career Development Fellowship toRM.

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