ANUNSUNGHow theEnteric Nervous SystemFights InfectionBY CHRISTINA HIJIYAPHOTOGRAPH COURTSEY OF WIKIPEDIAA color-enhanced scanning electron micrographshowing Salmonella Typhimurium (red) invadingcultured human cells.
When we think about infection, we thinkabout microscopic drama: the immunesystem as the sole guardians of our bodies;white blood cells as staunch defendersagainst pathogenic invaders. However,while B cells hunt for antigen-presentingcells and phagocytes swallow bacteriawhole, there has been a hidden accomplicein our bodies’ defense from infection: thenerves that line our intestines.In contrast to the bacteria-destroyingimmune system, the intestines harborthe peaceful presence of commensalmicroflora, friendly gut bacteria thathelp the body digest food and producevitamins. However, the amicableexistence of the gut microbiota survivesin delicate balance with the ruthlesselimination of pathogenic microbes. Thiscomplex equilibrium relies on signalingbetween cells in the immune system andintestinal cells that form the mucosalbarrier, which segregates gut bacteriafrom immune cells to avoid unnecessaryimmune responses. Until now, scientistshave thought that these two cell typeswere the lone ringleaders in the synthesisof bactericidal proteins and moleculesthat ward off threatening infections.Earlier this month, scientists at theYale School of Medicine, in collaborationwith researchers at Harvard MedicalSchool, discovered that neurons in theintestinal nervous system play a crucialrole in governing immune response in theintestines. Moreover, they observed thatthis antimicrobial function of intestinalneurons was non-redundant, potentiallyrevealing another key player in thestruggle against infections of the intestine.What is the Enteric Nervous System?There are a variety of different cell typesin the intestine. Epithelial cells form theborder on the inside of your intestinewhere food passes through, while outsideintestinal tissue contains immune cells thatdetect and target bacteria. Until now, thewide network of intestinal neurons, calledthe enteric nervous system (ENS), wasoften overlooked in gut immunity research.“There are actually more neurons in yourintestine than in your brain, so it’s veryneuron-dense,” said Abigail Jarret, firstauthor of the paper and a PhD candidatein Immunobiology at the Yale UniversitySchool of Medicine. The ENS has evenbeen described as a “second brain,” able tooperate autonomously and communicatewith the central nervous system to maintainthe delicate homeostasis in the intestine.The brain-gut axis, referring to thebidirectional link between the centralnervous system and the ENS, has recentlybecome a point of conversation in thescientific community. Because of this,scientists have also begun to explore howthe nervous system might influence theimmune response to infection.“Up until maybe five years ago...we [made] these beautiful plots of theintestines, and we only put epithelial cellsthere as a reference for the structure,and ... everything else was immune cellsand empty space,” said Esen Sefik, apostdoctoral fellow at the Yale School ofMedicine and a co-author of the paper.But the community started to becomeinterested in that empty space. Over time,scientific interest in the intestine grewfrom epithelial cells to other cell types, andmore recently, cells in the nervous system.This study stemmed from an interest inunderstanding the relationship betweenepithelial cells—the first line of defenseagainst infection by bacteria in the gutmicrobiota—and neurons in the ENS.Single Cytokine, Substantial SignificanceHirschsprung disease is a birth defectcharacterized by missing nerves in theintestine. A characteristic complicationof this disease is inflammative overgrowthof the microbiota, which indicates aprofound relationship between theENS and the mucosal barrier. Takenwith studies reporting that the ENScontributes to intestinal inflammation,responds to pathogenic infection, andtriggers effects on bactericidal proteinsecretions by epithelial cells, the authorsof the study were inspired to investigatethe role of the ENS in regulating mucosalbarrier immunity in the intestine.In immune cells, cytokines act aschemical messengers that cells use to talk toeach other, in order to regulate the immuneresponse. An especially important cytokinein the separation of the gut microbiotafrom the immune system is Interleukin-18(IL-18), which helps to recruit other cellsto clear bacterial infection. Around thirtyyears ago, scientists genetically modifiedthe first mouse that completely lackedChemical Biologythe ability to produce IL-18. When theyinfected it with intestinal salmonella, itdied. Many years later, a version of themouse was created that lacked IL-18 onlyin specific cells, allowing researchers tofurther study the role of different cell typesin the immune response.“I think people become very interestedin the function of a single cytokine or asingle molecule because as biologists, wewant to understand why we evolved tohave it,” Jarret said. “Why is lacking onething making these mice so sick? Whenwe had the ability to delete this gene inspecific cell populations, we could startto understand the contribution of thatmolecule from different cell sources.”Secretion and DeletionFOCUSTo further understand how differentsources of IL-18 contribute to protectionagainst infection, the researchers testedmouse strains that lacked IL-18 in differentcell populations. They infected each strainwith Salmonella typhimurium, a bacteriumthat targets the intestine, typically acquiredthrough contaminated water or food.When mice could not produce IL-18 intheir epithelial and immune cells, they werenot susceptible to salmonella infection.Surprisingly, when IL-18 was deleted fromintestinal neurons alone, mice displayedsymptoms associated with salmonellainfection. This helped the researchersdetermine that neuronal IL-18 is essentialfor preventing bacterial infection in a waythat epithelial and immune cells cannot.Next, the researchers sought todetermine how IL-18 protected micefrom bacterial infection. The researchersused RNA sequencing (RNA-Seq) tounderstand whether unique cellularsignaling events were present in neuronalIL-18-deficient mice compared to micethat lacked the cytokine in other celltypes. Using RNA-Seq, the researcherscould determine the presence andquantity of RNA in intestinal tissuesamples to analyze differences in geneexpression between different IL-18-deficient mice strains. RNA-Seq revealedthat in mice lacking IL-18 secretion fromneurons, the expression of bactericidaland antimicrobial genes that produceproteins vital to the immune responsewere exclusively reduced, rendering themice susceptible to salmonella infection.www.yalescientific.orgMarch 2020Yale Scientific Magazine13
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