Abstract

Necrotizingenterocolitis(NEC)istheleadingcauseofdeathfromgastrointestinaldiseaseinprematureinfants andischaracterizedbyanuncontrolledinflammatoryresponse.Thelackofunderstandingofthemechanisms thatregulatetheviciousinflammatorycascade,theinabilitytodeterminewhichinfantsaresusceptibletoNEC andalackoftherapeutictargetsallcontributetothepersistentlyhighmortalityrate.Thegoalsofthe proposedresearcharetodeterminethemechanismsthatregulatethepathologicimmuneresponse duringNECandusethisknowledgetodesignnovelepithelial-orimmune-specificstrategiesforthis devastatingdisease.Ourlaboratoryhasrecentlydiscoveredthattheinterleukin-22(IL-22)signalingpathway playsacriticalroleinattenuatingtheinflammatoryresponseduringNEC,asmicelackingthereceptorforIL-22 (IL-22Ra1)ontheintestinalepitheliumdemonstrateacceleratedmortalityinaneonatalmousemodelofNEC- likeintestinalinjury.WedemonstratethatmicesubjectedtoexperimentalNECdevelopgrossevidenceof smallintestinalischemiaandnecrosis,thatcanbecompletelyrescuedinmicewithintactIL-22signalingby administeringrecombinantIL-22.Inseekingtodeterminethemechanismsmediatingthisprotection,wehave demonstratedthattreatmentwithrecombinantIL-22decreasesthepro-inflammatoryTh17lymphocytic infiltrate,whichwehaveshowncontributestoNECpathogenesis.Furthermore,wealsodeterminedthatIL-22 signalingisimportantintheregulationofintestinalstemcelldifferentiation,asmicedeficientinIL-22Ra1inthe intestinedemonstrateanabnormallyprofoundphenotypecharacterizedbydecreasednumbersofsecretory cellsintheintestineaswellasdecreasedexpressionofcriticalgenesinvolvedinintestinalstemcell developmentandhostdefense.Basedonthesefindings,wehypothesizethatIL-22signalingthroughthe receptorIL-22Ra1attenuatesNECby1)enhancingintestinalstemcellfunction,2)increasinggobletcell differentiationand3)shiftingtheimmunecellrepertoiretowardsananti-inflammatoryphenotype.Wewill completeouraimsofthisprojectbybringingtogetheramulti-disciplinaryteamwithexpertiseinepithelial biology,mucosalimmunology,masscytometry,next-generationsequencing,high-resolutionconfocaland intravitalmicroscopyaswellasmicrofluidicsandengineeringforthederivationofinvitromodelsofhuman intestinalfunctionusinggut-on-a-chipdevices.Thesestudieswillmakeasignificantconceptualadvancein understandingthesignalingpathwaysinvolvedinattenuatingNEC,explainingtheuniquesusceptibilityofthe prematureinfanttoNECbasedonadefectinIL-22signaling,andwewillevaluateanoveltherapeuticstrategy forNECbyintroducingtheanti-inflammatorycytokineIL-22intheintestinalmilieu.

Public Health Relevance

Necrotizingenterocolitis(NEC)isadevastatingdiseaseofprematureinfantscharacterizedbyanexaggerated immuneresponse.Thisproposalaimstoidentifythemechanismsthatregulatethepathologicimmune responseduringNECandinterrogatewaystoattenuatetheinflammationthroughnoveltherapeuticstrategies. Thesestudieswillalsoenhanceourunderstandingoftheinteractionswithintheintestinalmicroenvironment duringNECusinganinnovativegut-on-a-chipplatform.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK118568-03
Application #
10001502
Study Section
Gastrointestinal Mucosal Pathobiology Study Section (GMPB)
Program Officer
Perrin, Peter J
Project Start
2018-09-01
Project End
2023-08-31
Budget Start
2020-09-01
Budget End
2021-08-31
Support Year
3
Fiscal Year
2020
Total Cost
Indirect Cost

  Institution

Name
Washington University
Department
Pediatrics
Type
Schools of Medicine
DUNS #
068552207
City
Saint Louis
State
MO
Country
United States
Zip Code
63130

  Publications

Mara, Madison A; Good, Misty; Weitkamp, Joern-Hendrik (2018) Innate and adaptive immunity in necrotizing enterocolitis. Semin Fetal Neonatal Med 23:394-399