Caspase-8 controls the gut response to microbial challenges by Tnf-α-dependent and independent pathways.
OBJECTIVE
Intestinal epithelial cells (IEC) express toll-like receptors (TLR) that facilitate microbial recognition. Stimulation of TLR ligands induces a transient increase in epithelial cell shedding, a mechanism that serves the antibacterial and antiviral host defence of the epithelium and promotes elimination of intracellular pathogens. Although activation of the extrinsic apoptosis pathway has been described during inflammatory shedding, its functional involvement is currently unclear.


METHODS
We investigated the functional involvement of caspase-8 signalling in microbial-induced intestinal cell shedding by injecting Lipopolysaccharide (LPS) to mimic bacterial pathogens and poly(I:C) as a probe for RNA viruses in vivo.


RESULTS
TLR stimulation of IEC was associated with a rapid activation of caspase-8 and increased epithelial cell shedding. In mice with an epithelial cell-specific deletion of caspase-8 TLR stimulation caused Rip3-dependent epithelial necroptosis instead of apoptosis. Mortality and tissue damage were more severe in mice in which IECs died by necroptosis than apoptosis. Inhibition of receptor-interacting protein (Rip) kinases rescued the epithelium from TLR-induced gut damage. TLR3-induced necroptosis was directly mediated via TRIF-dependent pathways, independent of Tnf-α and type III interferons, whereas TLR4-induced tissue damage was critically dependent on Tnf-α.


CONCLUSIONS
Together, our data demonstrate an essential role for caspase-8 in maintaining the gut barrier in response to mucosal pathogens by permitting inflammatory shedding and preventing necroptosis of infected cells. These data suggest that therapeutic strategies targeting the cell death machinery represent a promising new option for the treatment of inflammatory and infective enteropathies.
Medical Clinic 1, Friedrich Alexander University, Erlangen, Germany.
Claudia
C
Günther
Medical Clinic 1, Friedrich Alexander University, Erlangen, Germany.
Barbara
B
Buchen
Medical Clinic 1, Friedrich Alexander University, Erlangen, Germany.
Gui-Wei
GW
He
Institute for Medical Microbiology and Hospital Epidemiology, Hannover Medical School, Hannover, Germany.
Mathias
M
Hornef
Institute for Medical Microbiology and Hospital Epidemiology, Hannover Medical School, Hannover, Germany.
Natalia
N
Torow
Medical Clinic 1, Friedrich Alexander University, Erlangen, Germany.
Helmut
H
Neumann
Medical Clinic 1, Friedrich Alexander University, Erlangen, Germany.
Nadine
N
Wittkopf
Medical Clinic 1, Friedrich Alexander University, Erlangen, Germany.
Eva
E
Martini
Institute for Laboratory Animal Science and Central Animal Facility, Hannover Medical School, Hannover, Germany.
Marijana
M
Basic
Institute for Laboratory Animal Science and Central Animal Facility, Hannover Medical School, Hannover, Germany.
André
A
Bleich
Norwich Medical School, University of East Anglia, Norwich, UK.
Alastair J M
AJ
Watson
Medical Clinic 1, Friedrich Alexander University, Erlangen, Germany.
Markus F
MF
Neurath
Medical Clinic 1, Friedrich Alexander University, Erlangen, Germany.
Christoph
C
Becker
D000818:Animals; D053181:Caspase 8 / Q000502:physiology*; D004847:Epithelial Cells / Q000502:physiology*; D007413:Intestinal Mucosa / Q000382:microbiology* / Q000502:physiology*; D051379:Mice; D015398:Signal Transduction; D014409:Tumor Necrosis Factor-alpha / Q000502:physiology*
D014409:Tumor Necrosis Factor-alpha; D053181:Caspase 8
Apoptosis; Cell Biology; Cell Death; Intestinal Epithelium; TNF