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IKK? promotes intestinal tumorigenesis by limiting recruitment of M1-like polarized myeloid cells.

ABSTRACT: The recruitment of immune cells into solid tumors is an essential prerequisite of tumor development. Depending on the prevailing polarization profile of these infiltrating leucocytes, tumorigenesis is either promoted or blocked. Here, we identify I?B kinase ? (IKK?) as a central regulator of a tumoricidal microenvironment during intestinal carcinogenesis. Mice deficient in IKK? kinase activity are largely protected from intestinal tumor development that is dependent on the enhanced recruitment of interferon ? (IFN?)-expressing M1-like myeloid cells. In IKK? mutant mice, M1-like polarization is not controlled in a cell-autonomous manner but, rather, depends on the interplay of both IKK? mutant tumor epithelia and immune cells. Because therapies aiming at the tumor microenvironment rather than directly at the mutated cancer cell may circumvent resistance development, we suggest IKK? as a promising target for colorectal cancer (CRC) therapy.

SUBMITTER: Goktuna SI

PROVIDER: S-EPMC7676455 | biostudies-literature | 2014 Jun

REPOSITORIES: biostudies-literature

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IKKα promotes intestinal tumorigenesis by limiting recruitment of M1-like polarized myeloid cells.

Göktuna Serkan I SI Canli Ozge O Bollrath Julia J Fingerle Alexander A AA Horst David D Diamanti Michaela A MA Pallangyo Charles C Bennecke Moritz M Nebelsiek Tim T Mankan Arun K AK Lang Roland R Artis David D Hu Yinling Y Patzelt Thomas T Ruland Jürgen J Kirchner Thomas T Taketo M Mark MM Chariot Alain A Arkan Melek C MC Greten Florian R FR

Cell reports 20140529 6

The recruitment of immune cells into solid tumors is an essential prerequisite of tumor development. Depending on the prevailing polarization profile of these infiltrating leucocytes, tumorigenesis is either promoted or blocked. Here, we identify IκB kinase α (IKKα) as a central regulator of a tumoricidal microenvironment during intestinal carcinogenesis. Mice deficient in IKKα kinase activity are largely protected from intestinal tumor development that is dependent on the enhanced recruitment o ...[more]

PMID: 24882009

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Project description:Background & aimsThe intestinal epithelium functions both in nutrient absorption and as a barrier, separating the luminal contents from a network of vascular, fibroblastic, and immune cells underneath. After injury to the intestine, multiple cell populations cooperate to drive regeneration of the mucosal barrier, including lymphatic endothelial cells (LECs). A population of granulocytic immature myeloid cells (IMCs), marked by Hdc, participate in regeneration of multiple organs such as the colon and central nervous system, and their contribution to intestinal regeneration was investigated.MethodsBy using male and female histidine decarboxylase (Hdc) green fluorescent reporter (GFP) mice, we investigated the role of Hdc+ IMCs in intestinal regeneration after exposure to 12 Gy whole-body irradiation. The movement of IMCs was analyzed using flow cytometry and immunostaining. Ablation of Hdc+ cells using the HdcCreERT2 tamoxifen-inducible recombinase Cre system, conditional knockout of Prostaglandin-endoperoxidase synthase 2 (Ptgs2) in Hdc+ cells using HdcCre; Ptgs2 floxed mice, and visualization of LECs using Prox1tdTomato mice also was performed. The role of microbial signals was investigated by knocking down mice gut microbiomes using antibiotic cocktail gavages.ResultsWe found that Hdc+ IMCs infiltrate the injured intestine after irradiation injury and promote epithelial regeneration in part by modulating LEC activity. Hdc+ IMCs express Ptgs2 (encoding cyclooxygenase-2/COX-2), and enables them to produce prostaglandin E2. Prostaglandin E2 acts on the prostaglandin E2 receptor 4 receptor (EP4) on LECs to promote lymphangiogenesis and induce the expression of proregenerative factors including R-spondin 3. Depletion of gut microbes leads to reduced intestinal regeneration by impaired recruitment of IMCs.ConclusionsAltogether, our results unveil a critical role for IMCs in intestinal repair by modulating LEC activity and implicate gut microbes as mediators of intestinal regeneration.

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IKK? promotes intestinal tumorigenesis by limiting recruitment of M1-like polarized myeloid cells.

Publications

IKKα promotes intestinal tumorigenesis by limiting recruitment of M1-like polarized myeloid cells.

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