RESUMO
Microbiota play critical roles in regulating colitis and colorectal cancer (CRC). However, it is unclear how the microbiota generate protective immunity against these disease states. Here, we find that loss of the innate and adaptive immune signaling molecule, TAK1, in myeloid cells (Tak1ΔM/ΔM) yields complete resistance to chemical-induced colitis and CRC through microbiome alterations that drive protective immunity. Tak1ΔM/ΔM mice exhibit altered microbiota that are critical for resistance, with antibiotic-mediated disruption ablating protection and Tak1ΔM/ΔM microbiota transfer conferring protection against colitis or CRC. The altered microbiota of Tak1ΔM/ΔM mice promote IL-1ß and IL-6 signaling pathways, which are required for induction of protective intestinal Th17 cells and resistance. Specifically, Odoribacter splanchnicus is abundant in Tak1ΔM/ΔM mice and sufficient to induce intestinal Th17 cell development and confer resistance against colitis and CRC in wild-type mice. These findings identify specific microbiota strains and immune mechanisms that protect against colitis and CRC.
Assuntos
Bacteroidetes/metabolismo , Colite/microbiologia , Neoplasias Colorretais/microbiologia , Citocinas/fisiologia , Microbioma Gastrointestinal , MAP Quinase Quinase Quinases/fisiologia , Células Th17/metabolismo , Animais , Colite/induzido quimicamente , Colite/metabolismo , Neoplasias Colorretais/induzido quimicamente , Neoplasias Colorretais/metabolismo , Modelos Animais de Doenças , Fezes/microbiologia , Feminino , Interações entre Hospedeiro e Microrganismos , Imunidade Inata , Interleucina-1beta/fisiologia , Interleucina-6/fisiologia , MAP Quinase Quinase Quinases/genética , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Células Mieloides/metabolismo , Transdução de Sinais , Células Th17/imunologiaRESUMO
Transforming growth factor ß-activated kinase 1 (TAK1 or MAP3K7) is a key signaling component of nuclear factor-κB (NF-κB) and mitogen-activated protein kinase (MAPK) signaling pathways. Activation of TAK1 is tightly regulated through its binding partners and protein modifications. Although TAK1 functions as an essential and positive regulator of innate immune signaling and apoptosis in mouse embryonic fibroblasts (MEFs), T cells, and other cells, it negatively regulates cell development and activation of proinflammatory signaling pathways in neutrophils. However, the molecular mechanisms responsible for the opposite roles of TAK1 in different cell types remain to be addressed. In this article, we discuss the latest progresses in our understanding of TAK1 regulation, function, and mechanisms in a cell-type specific manner.