Toll-like receptor 4-mediated regulation of spontaneous Helicobacter-dependent colitis in IL-10-deficient mice.
OBJECTIVE
The commensal microbiota is believed to have an important role in regulating immune responsiveness and preventing intestinal inflammation. Intestinal microbes produce signals that regulate inflammation via Toll-like receptor (TLR) signaling, but the mechanisms of this process are poorly understood. We investigated the role of the anti-inflammatory cytokine interleukin (IL)-10 in this signaling pathway using a mouse model of colitis.


METHODS
Clinical, histopathologic, and functional parameters of intestinal inflammation were evaluated in TLR4(-/-), IL-10(-/-), and TLR4(-/-) x IL-10(-/-) mice that were free of specific pathogens and in TLR4(-/-) x IL-10(-/-) mice following eradication and reintroduction of Helicobacter hepaticus. Regulatory T-cell (Treg) function was evaluated by crossing each of the lines with transgenic mice that express green fluorescent protein under control of the endogenous regulatory elements of Foxp3. Apoptotic cells in the colonic lamina propria were detected by a TUNEL assay.


RESULTS
TLR4-mediated signals have 2 interrelated roles in promoting inflammation in TLR4(-/-) x IL-10(-/-) mice. In the absence of TLR4-mediated signals, secretion of proinflammatory and immunoregulatory cytokines is dysregulated. Tregs (Foxp3(+)) that secrete interferon-gamma and IL-17 accumulate in the colonic lamina propria of TLR4(-/-) x IL-10(-/-) mice and do not prevent inflammation. Aberrant control of epithelial cell turnover results in the persistence of antigen-presenting cells that contain apoptotic epithelial fragments in the colonic lamina propria of Helicobacter-infected TLR4(-/-) mice.


CONCLUSIONS
In mice that lack both IL-10- and TLR4-mediated signals, aberrant regulatory T-cell function and dysregulated control of epithelial homeostasis combine to exacerbate intestinal inflammation.
Matharu
Kabir S
KS
Center for the Study of Inflammatory Bowel Disease, Massachusetts General Hospital, Boston, Massachusetts, USA.
Mizoguchi
Emiko
E
Cotoner
Carmen Alonso
CA
Nguyen
Deanna D
DD
Mingle
Bethany
B
Iweala
Onyinye I
OI
McBee
Megan E
ME
Stefka
Andrew T
AT
Prioult
Guenolee
G
Haigis
Kevin M
KM
Bhan
Atul K
AK
Snapper
Scott B
SB
Murakami
Hidehiro
H
Schauer
David B
DB
Reinecker
Hans-Christian
HC
Mizoguchi
Atsushi
A
Nagler
Cathryn R
CR
D000818:Animals; D017209:Apoptosis; D003092:Colitis / Q000276:immunology* / Q000382:microbiology / Q000473:pathology / Q000517:prevention & control; D004195:Disease Models, Animal; D004847:Epithelial Cells / Q000276:immunology* / Q000382:microbiology / Q000473:pathology; D051858:Forkhead Transcription Factors / Q000235:genetics; D017930:Genes, Reporter; D049452:Green Fluorescent Proteins / Q000235:genetics; D016481:Helicobacter Infections / Q000276:immunology / Q000382:microbiology* / Q000473:pathology; D044923:Helicobacter hepaticus / Q000276:immunology*; D018836:Inflammation Mediators / Q000378:metabolism*; D007371:Interferon-gamma / Q000378:metabolism; D016753:Interleukin-10 / Q000172:deficiency* / Q000235:genetics; D020381:Interleukin-17 / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D012005:Rectal Prolapse / Q000276:immunology / Q000382:microbiology; D013154:Spleen / Q000276:immunology / Q000382:microbiology; D050378:T-Lymphocytes, Regulatory / Q000276:immunology* / Q000382:microbiology; D018417:Th1 Cells / Q000276:immunology / Q000382:microbiology; D013997:Time Factors; D051197:Toll-Like Receptor 4 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*
D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; D018836:Inflammation Mediators; D020381:Interleukin-17; C493487:Tlr4 protein, mouse; D051197:Toll-Like Receptor 4; D016753:Interleukin-10; D049452:Green Fluorescent Proteins; D007371:Interferon-gamma