PMID- 29760082
OWN - NLM
STAT- MEDLINE
DCOM- 20180904
LR  - 20191218
IS  - 1091-6490 (Electronic)
IS  - 0027-8424 (Print)
IS  - 0027-8424 (Linking)
VI  - 115
IP  - 22
DP  - 2018 May 29
TI  - A cytokine network involving IL-36gamma, IL-23, and IL-22 promotes antimicrobial 
      defense and recovery from intestinal barrier damage.
PG  - E5076-E5085
LID - 10.1073/pnas.1718902115 [doi]
AB  - The gut epithelium acts to separate host immune cells from unrestricted 
      interactions with the microbiota and other environmental stimuli. In response to 
      epithelial damage or dysfunction, immune cells are activated to produce 
      interleukin (IL)-22, which is involved in repair and protection of barrier 
      surfaces. However, the specific pathways leading to IL-22 and associated 
      antimicrobial peptide (AMP) production in response to intestinal tissue damage 
      remain incompletely understood. Here, we define a critical IL-36/IL-23/IL-22 
      cytokine network that is instrumental for AMP production and host defense. Using 
      a murine model of intestinal damage and repair, we show that IL-36gamma is a potent 
      inducer of IL-23 both in vitro and in vivo. IL-36gamma-induced IL-23 required 
      Notch2-dependent (CD11b(+)CD103(+)) dendritic cells (DCs), but not 
      Batf3-dependent (CD11b(-)CD103(+)) DCs or CSF1R-dependent macrophages. The 
      intracellular signaling cascade linking IL-36 receptor (IL-36R) to IL-23 
      production by DCs involved MyD88 and the NF-kappaB subunits c-Rel and p50. Consistent 
      with in vitro observations, IL-36R- and IL-36gamma-deficient mice exhibited 
      dramatically reduced IL-23, IL-22, and AMP levels, and consequently failed to 
      recover from acute intestinal damage. Interestingly, impaired recovery of mice 
      deficient in IL-36R or IL-36gamma could be rescued by treatment with exogenous IL-23. 
      This recovery was accompanied by a restoration of IL-22 and AMP expression in the 
      colon. Collectively, these data define a cytokine network involving IL-36gamma, 
      IL-23, and IL-22 that is activated in response to intestinal barrier damage and 
      involved in providing critical host defense.
FAU - Ngo, Vu L
AU  - Ngo VL
AD  - Center for Inflammation, Immunity & Infection, Institute for Biomedical Sciences, 
      Georgia State University, Atlanta, GA 30303.
FAU - Abo, Hirohito
AU  - Abo H
AD  - Center for Inflammation, Immunity & Infection, Institute for Biomedical Sciences, 
      Georgia State University, Atlanta, GA 30303.
FAU - Maxim, Estera
AU  - Maxim E
AD  - Center for Inflammation, Immunity & Infection, Institute for Biomedical Sciences, 
      Georgia State University, Atlanta, GA 30303.
FAU - Harusato, Akihito
AU  - Harusato A
AD  - Center for Inflammation, Immunity & Infection, Institute for Biomedical Sciences, 
      Georgia State University, Atlanta, GA 30303.
FAU - Geem, Duke
AU  - Geem D
AD  - Center for Inflammation, Immunity & Infection, Institute for Biomedical Sciences, 
      Georgia State University, Atlanta, GA 30303.
FAU - Medina-Contreras, Oscar
AU  - Medina-Contreras O
AD  - Center for Inflammation, Immunity & Infection, Institute for Biomedical Sciences, 
      Georgia State University, Atlanta, GA 30303.
FAU - Merlin, Didier
AU  - Merlin D
AD  - Center for Diagnostics and Therapeutics, Institute for Biomedical Sciences, 
      Georgia State University, Atlanta, GA 30303.
AD  - Atlanta Veterans Affairs Medical Center, Decatur, GA 30033.
FAU - Gewirtz, Andrew T
AU  - Gewirtz AT
AD  - Center for Inflammation, Immunity & Infection, 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 - Denning, Timothy L
AU  - Denning TL
AD  - Center for Inflammation, Immunity & Infection, Institute for Biomedical Sciences, 
      Georgia State University, Atlanta, GA 30303; tdenning@gsu.edu.
LA  - eng
GR  - R01 DK055679/DK/NIDDK NIH HHS/United States
GR  - R01 DK097256/DK/NIDDK NIH HHS/United States
GR  - R01 DK107739/DK/NIDDK NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
PT  - Research Support, U.S. Gov't, Non-P.H.S.
DEP - 20180514
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 (Interleukins)
SB  - IM
MH  - Animals
MH  - Immunity, Innate/*immunology
MH  - Inflammatory Bowel Diseases/*immunology/metabolism
MH  - Interleukins/genetics/*immunology/metabolism
MH  - Intestinal Mucosa/immunology/metabolism
MH  - Mice
MH  - Mice, Transgenic
MH  - Wound Healing/*immunology
PMC - PMC5984499
OTO - NOTNLM
OT  - inflammatory bowel disease
OT  - innate immunity
OT  - interleukin
OT  - repair
COIS- The authors declare no conflict of interest.
EDAT- 2018/05/16 06:00
MHDA- 2018/09/05 06:00
PMCR- 2018/11/29
CRDT- 2018/05/16 06:00
PHST- 2018/05/16 06:00 [pubmed]
PHST- 2018/09/05 06:00 [medline]
PHST- 2018/05/16 06:00 [entrez]
PHST- 2018/11/29 00:00 [pmc-release]
AID - 1718902115 [pii]
AID - 201718902 [pii]
AID - 10.1073/pnas.1718902115 [doi]
PST - ppublish
SO  - Proc Natl Acad Sci U S A. 2018 May 29;115(22):E5076-E5085. doi: 
      10.1073/pnas.1718902115. Epub 2018 May 14.