PMID- 33087566
OWN - NLM
STAT- MEDLINE
DCOM- 20210107
LR  - 20240214
IS  - 1091-6490 (Electronic)
IS  - 0027-8424 (Print)
IS  - 0027-8424 (Linking)
VI  - 117
IP  - 44
DP  - 2020 Nov 3
TI  - IL-36R signaling integrates innate and adaptive immune-mediated protection 
      against enteropathogenic bacteria.
PG  - 27540-27548
LID - 10.1073/pnas.2004484117 [doi]
AB  - Enteropathogenic bacterial infections are a global health issue associated with 
      high mortality, particularly in developing countries. Efficient host protection 
      against enteropathogenic bacterial infection is characterized by coordinated 
      responses between immune and nonimmune cells. In response to infection in mice, 
      innate immune cells are activated to produce interleukin (IL)-23 and IL-22, which 
      promote antimicrobial peptide (AMP) production and bacterial clearance. IL-36 
      cytokines are proinflammatory IL-1 superfamily members, yet their role in 
      enteropathogenic bacterial infection remains poorly defined. Using the enteric 
      mouse pathogen, C.rodentium, we demonstrate that signaling via IL-36 receptor 
      (IL-36R) orchestrates a crucial innate-adaptive immune link to control bacterial 
      infection. IL-36R-deficient mice (Il1rl2(-/-) ) exhibited significant impairment 
      in expression of IL-22 and AMPs, increased intestinal damage, and failed to 
      contain C. rodentium compared to controls. These defects were associated with 
      failure to induce IL-23 and IL-6, two key IL-22 inducers in the early and late 
      phases of infection, respectively. Treatment of Il1rl2(-/-) mice with IL-23 
      during the early phase of C. rodentium infection rescued IL-22 production from 
      group 3 innate lymphoid cells (ILCs), whereas IL-6 administration during the late 
      phase rescued IL-22-mediated production from CD4(+) T cell, and both treatments 
      protected Il1rl2(-/-) mice from uncontained infection. Furthermore, 
      IL-36R-mediated IL-22 production by CD4(+) T cells was dependent upon NFkappaB-p65 
      and IL-6 expression in dendritic cells (DCs), as well as aryl hydrocarbon 
      receptor (AhR) expression by CD4(+) T cells. Collectively, these data demonstrate 
      that the IL-36 signaling pathway integrates innate and adaptive immunity leading 
      to host defense against enteropathogenic bacterial infection.
FAU - Ngo, Vu L
AU  - Ngo VL
AD  - Institute for Biomedical Sciences, Georgia State University, Atlanta, GA 30303.
FAU - Abo, Hirohito
AU  - Abo H
AD  - Institute for Biomedical Sciences, Georgia State University, Atlanta, GA 30303.
FAU - Kuczma, Michal
AU  - Kuczma M
AUID- ORCID: 0000-0003-2310-3590
AD  - Institute for Biomedical Sciences, Georgia State University, Atlanta, GA 30303.
FAU - Szurek, Edyta
AU  - Szurek E
AD  - Institute for Biomedical Sciences, Georgia State University, Atlanta, GA 30303.
FAU - Moore, Nora
AU  - Moore N
AD  - Institute for Biomedical Sciences, Georgia State University, Atlanta, GA 30303.
FAU - Medina-Contreras, Oscar
AU  - Medina-Contreras O
AD  - Institute for Biomedical Sciences, Georgia State University, Atlanta, GA 30303.
FAU - Nusrat, Asma
AU  - Nusrat A
AD  - Department of Pathology, University of Michigan, Ann Arbor, MI 48109.
FAU - Merlin, Didier
AU  - Merlin D
AD  - Institute for Biomedical Sciences, Georgia State University, Atlanta, GA 30303.
FAU - Gewirtz, Andrew T
AU  - Gewirtz AT
AD  - Institute for Biomedical Sciences, Georgia State University, Atlanta, GA 30303.
FAU - Ignatowicz, Leszek
AU  - Ignatowicz L
AUID- ORCID: 0000-0001-8666-0381
AD  - Institute for Biomedical Sciences, Georgia State University, Atlanta, GA 30303.
FAU - Denning, Timothy L
AU  - Denning TL
AD  - Institute for Biomedical Sciences, Georgia State University, Atlanta, GA 30303; 
      tdenning@gsu.edu.
LA  - eng
GR  - R01 DK107739/DK/NIDDK NIH HHS/United States
GR  - R01 DK120907/DK/NIDDK NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, U.S. Gov't, Non-P.H.S.
DEP - 20201021
PL  - United States
TA  - Proc Natl Acad Sci U S A
JT  - Proceedings of the National Academy of Sciences of the United States of America
JID - 7505876
RN  - 0 (Interleukin-1)
RN  - 0 (Receptors, Interleukin-1)
RN  - 0 (interleukin-36 receptor, mouse)
RN  - 0 (interleukin-36, mouse)
SB  - IM
MH  - *Adaptive Immunity
MH  - Animals
MH  - Citrobacter rodentium/*immunology/pathogenicity
MH  - Disease Models, Animal
MH  - Enterobacteriaceae Infections/*immunology/microbiology
MH  - *Immunity, Innate
MH  - Interleukin-1/metabolism
MH  - Intestinal Mucosa/immunology/metabolism/microbiology
MH  - Mice
MH  - Mice, Knockout
MH  - Receptors, Interleukin-1/genetics/*metabolism
MH  - Signal Transduction/genetics/immunology
PMC - PMC7959549
OTO - NOTNLM
OT  - adaptive immunity
OT  - bacterial infection
OT  - innate immunity
OT  - interleukin
COIS- The authors declare no competing interest.
EDAT- 2020/10/23 06:00
MHDA- 2021/01/08 06:00
PMCR- 2021/04/21
CRDT- 2020/10/22 05:29
PHST- 2020/10/23 06:00 [pubmed]
PHST- 2021/01/08 06:00 [medline]
PHST- 2020/10/22 05:29 [entrez]
PHST- 2021/04/21 00:00 [pmc-release]
AID - 2004484117 [pii]
AID - 202004484 [pii]
AID - 10.1073/pnas.2004484117 [doi]
PST - ppublish
SO  - Proc Natl Acad Sci U S A. 2020 Nov 3;117(44):27540-27548. doi: 
      10.1073/pnas.2004484117. Epub 2020 Oct 21.