CCR6–CCL20-Mediated Immunologic Pathways in Inflammatory Bowel Disease
Abstract
:1. Introduction
2. Chemokines
Chemokine Receptor 6 (CCR6) and Chemokine Ligand CCL20
3. Importance of IBD
4. Immune Mechanisms of CCR6–CCL20
Immune Mechanisms of CCR6–CCL20 Specific to IBD
5. Immunologic Pathways in IBD Involving CCR6
5.1. TH1/TH2 Pathway
5.2. TH1/TH17 Pathway
5.3. TH17/Treg
5.4. IL-23/IL-17 Pathway
5.5. Akt/ERK-1/2 Pathway
5.6. Innate Lymphoid Cells (ILC)
5.7. TH9/TH2 Pathway
5.8. CD4+/CD8α+ Cells (DP8-Alpha Cells)
6. Future Directions
Author Contributions
Funding
Acknowledgments
Conflicts of Interest
Abbreviations
Akt | protein kinase B |
B | bursa-derived (lymphocyte) |
β defensin | beta defensin |
CD | Crohn’s disease |
CD4+ T | cluster of differentiation 4 positive thymocyte |
CcR6 | CC chemokine receptor 6 |
CCL20 | CC chemokine ligand 20 |
CCr6 | gene for CCR6 |
CCR6−/− | CCR6-deficient |
CRC | colorectal carcinoma |
DC | dendritic cell |
DNA | deoxyribonucleic acid |
DSS | dextran sodium sulphate |
ER | endoplasmic reticulum |
ERK | extracellular signal-regulated kinases |
FAE | follicle-associated epithelium |
FoxP3 | forkhead box P3 |
GALT | gut-associated lymphoid tissue |
GATA | transcription factor |
GI tract | gastrointestinal tract |
GM-CSF | granulocyte macrophage colony-stimulating factor |
GWAS | genome-wide association studies |
γδ T cell | gamma delta T cell |
HIV | human immunodeficiency virus |
IBD | inflammatory bowel disease |
IEC | intestinal epithelial cell |
IFN-γ | gamma interferon |
IL | interleukin |
IL-1β | interleukin one beta |
ILC3 | innate lymphoid cell 3 |
IRF | interferon regulatory factor protein |
JNK | Jun kinase |
KO | knockout |
LP | lamina propria |
LARC | liver and activation-regulated chemokine |
M cell | microfold cell |
MAPK | mitogen-activated protein kinase |
MEK | dual threonine and tyrosine recognition kinase |
MIP-3α | macrophage inflammatory protein-3 alpha |
NCR | natural cytotoxicity receptor |
NF-kB | nuclear factor kappa B |
NK | natural killer |
NOD | nucleotide-binding and oligomerization domain |
p | protein |
PBMC | peripheral blood mononuclear cells |
PI3K | phosphoinositide-3-kinase |
R | receptor |
Ras/Raf | guanine nucleotide exchange factor |
RNA | ribonucleic acid |
RORγt | retinoic-acid-receptor-related orphan nuclear receptor gamma |
SAPK | stress-activated protein kinase |
SCID | severe combined immune deficiency |
SNP | single nucleotide polymorphism |
STAT3 | signal transducer and activator of transcription 3 |
T | thymus-derived lymphocyte/thymocyte |
T-bet | T-box transcription factor |
Tg | transgenic |
TH1 | T helper 1 |
TH2 | T helper 2 |
TH17 | thymocyte helper 17 |
TGF-β | transforming growth factor-beta sulphate |
TNBS | trinitro benzene sulfonic acid |
TNF-α | tumour necrosis factor-alpha |
Treg | regulatory thymocyte cell |
UC | ulcerative colitis |
WT | wild type |
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Pathway | Link to CCR6 | Mechanism | Outcome | Reference |
---|---|---|---|---|
TH1/TH2 | CCR6+ TH1 cells | Migration of CCR6+ TH1 cells to the intestine, attracted by CCL20 produced by the IEC, given their release of proinflammatory cytokines induces inflammation in the intestine. | Inflammation | [33] |
TH1/TH17 | CCR6+ TH17 cells | Induced by IL-23, RORγt, and TGF-β, TH17 cells, upon differentiation, release IL-17A–F, which drives CCR6+ TH17 cell recruitment towards the intestinal epithelium, attracted by CCL20 produced by the IEC. | Inflammation | [32,33,34,35,36,37,38,39,40] |
TH17/Treg | CCR6+ Treg cells | Induced by TGF-β and FoxP3, regulatory Treg cells, after differentiation, release IL-10, which drives CCR6+ Treg cells towards the intestinal epithelium, attracted by CCL20 produced by the IEC. | Resolution | [40,41,42] |
IL-23/IL-17 | CCR6+ TH17 | IL-12, STAT3, and IL-23-induced CCR6+ TH17 cells migrate towards the intestinal epithelium, stimulated by IL-17A–F and attracted by CCL20 produced by the IEC. | Inflammation | [27,41,42] |
Akt/ERK-1/2 | CCR6+ TH17/Treg | CCL20 activates Akt/ERK-1/2 and SAPK/JNK MAP kinases to increase cell proliferation and cell mobilization in the intestinal epithelium. | Homeostasis | [42,43] |
ILC | CCR6+ NCR+ ILC3 | Induced by IL-22, CCR6+ NCR+ ILC3 release IL-12 and activate IFN-γ-producing ILC1 cells. | Inflammation | [44,45,46] |
IL-23-producing ILC1 activate NCR+ ILC3 to express MHC class II epitopes to initiate transformation of naïve T helper cells into effectors. | Inflammation/Resolution | |||
Induced by IL-22, CCR6+ ILC3 migrate to Peyer’s patches, attracted by CCL20 produced by the IEC. Decrease in IL-22 results in loss of immune tolerance. | ||||
TH9/TH2 | CCR6+ TH9 cells | Induced by retinoic acid, TGF-β and IL-10 released by ILC3 effect differentiation of Treg cells in the intestine. | Inflammation | [47,48] |
Induction by IL-9 elicits antiparasitic or allergic immunity, evoking a TH2-type immune response. |
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Ranasinghe, R.; Eri, R. CCR6–CCL20-Mediated Immunologic Pathways in Inflammatory Bowel Disease. Gastrointest. Disord. 2019, 1, 15-29. https://doi.org/10.3390/gidisord1010003
Ranasinghe R, Eri R. CCR6–CCL20-Mediated Immunologic Pathways in Inflammatory Bowel Disease. Gastrointestinal Disorders. 2019; 1(1):15-29. https://doi.org/10.3390/gidisord1010003
Chicago/Turabian StyleRanasinghe, Ranmali, and Rajaraman Eri. 2019. "CCR6–CCL20-Mediated Immunologic Pathways in Inflammatory Bowel Disease" Gastrointestinal Disorders 1, no. 1: 15-29. https://doi.org/10.3390/gidisord1010003