TNF receptor type I-dependent activation of innate responses to reduce intestinal damage-associated mortality.
OBJECTIVE
Ligation of tumor necrosis factor (TNF) receptors (TNFRs) with TNF plays a critical role in the pathogenesis of human inflammatory bowel disease (IBD). However, it remains unclear which cell types activated through TNFR-associated signaling cascades are involved in the pathogenesis of colitis.


METHODS
Recombination activating gene-1 (RAG) knockout (KO) (no T or B cells)-based TNFR double and triple KO mice were generated. Bone marrow (BM) chimera mice in which BM-derived myeloid cells, but not colonic epithelial cells (CECs), express TNFRs were also generated. Colitis was induced by administration of dextran sodium sulfate (DSS) in distilled water. Murine lines and chimeras were assessed for disease severity, histopathology, apoptotic cell rate, epithelial proliferation, and bacterial invasion rate.


RESULTS
Following DSS administration, mice lacking both RAG and TNFR1 exhibited a high mortality (>80%) rate with an impaired CEC regeneration compared with RAG KO and RAG x TNFR2 double KO (DKO) mice. Transplantation of RAG KO-derived BM cells restored CEC regeneration and rescued the majority of recipient RAG x TNFR1 DKO mice from DSS-induced mortality. After BM transplantation, RAG x TNFR1 DKO mice exhibited an increased rate of apoptosis in the colonic lamina propria macrophages in association with the activation of caspases. In addition, BM reconstitution directly or indirectly enhanced the proliferation of CECs by activating mitogen-activated protein kinase and phosphoinositide-3 kinase/Akt pathways.


CONCLUSIONS
TNFR1-signaling cascade in colonic myeloid lineage cells contributes to the suppression of acute damage-associated mortality presumably by controlling CEC homeostasis.
Mizoguchi
Emiko
E
Center for the Study of Inflammatory Bowel Disease, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA. emizoguchi@partners.org
Hachiya
Yuriko
Y
Kawada
Mayumi
M
Nagatani
Katsuya
K
Ogawa
Atsuhiro
A
Sugimoto
Ken
K
Mizoguchi
Atsushi
A
Podolsky
Daniel K
DK
D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D001853:Bone Marrow / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D016026:Bone Marrow Transplantation; D049109:Cell Proliferation; D003092:Colitis / Q000139:chemically induced / Q000235:genetics / Q000503:physiopathology*; D003106:Colon / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology*; D016264:Dextran Sulfate; D004195:Disease Models, Animal; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism; D006706:Homeostasis / Q000502:physiology; D007413:Intestinal Mucosa / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D047888:Receptors, Tumor Necrosis Factor, Type I / Q000235:genetics / Q000378:metabolism*; D047889:Receptors, Tumor Necrosis Factor, Type II / Q000235:genetics / Q000378:metabolism; D012720:Severity of Illness Index; D015398:Signal Transduction / Q000502:physiology
D018398:Homeodomain Proteins; D047888:Receptors, Tumor Necrosis Factor, Type I; D047889:Receptors, Tumor Necrosis Factor, Type II; C506236:Tnfrsf1a protein, mouse; C064658:RAG-1 protein; D016264:Dextran Sulfate