Multi-Scale In Vivo Systems Analysis Reveals the Influence of Immune Cells on TNF-a-Induced Apoptosis in the Intestinal Epithelium

Intestinal epithelial cells exist within a complex environment that affects how they interpret and respond to stimuli. We have applied a multi-scale in vivo systems approach to understand how intestinal immune cells communicate with epithelial cells to regulate responses to inflammatory signals. Multivariate modeling analysis of a large dataset composed of phospho-signals, cytokines, and immune cell populations within the intestine revealed an intimate relationship between immune cells and the epithelial response to TNF-a. Ablation of lymphocytes in the intestine prompted a decrease in the expression of MCP-1, which in turn increased the steady state number of intestinal plasmacytoid dendritic cells (pDCs). This change in the immune compartment affected the intestinal cytokine milieu and subsequent epithelial cell signaling network, with cells becoming hypersensitive to TNF-a-induced apoptosis in a way that could be predicted by mathematical modeling. In summary, we have uncovered a novel cellular network that regulates the response of intestinal epithelial cells to inflammatory stimuli in an in vivo setting. Citation: Lau KS, Cortez-Retamozo V, Philips SR, Pittet MJ, Lauffenburger DA, et al. (2012) Multi-Scale In Vivo Systems Analysis Reveals the Influence of Immune Cells on TNF-a-Induced Apoptosis in the Intestinal Epithelium. PLoS Biol 10(9): e1001393. doi:10.1371/journal.pbio.1001393 Academic Editor: Jerry R. McGhee, University of Alabama at Birmingham, United States of America Received May 24, 2012; Accepted August 7, 2012; Published September 25, 2012 Copyright: 2012 Lau et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Funding: This work was supported by grants from the National Institute of General Medical Sciences (R01-GM088827 to K.M.H., D.A.L.) and the National Cancer Institute (U54-CA112967 to D.A.L.). K.S.L. is a Robert Black Fellow of the Damon Runyon Cancer Research Foundation. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Competing Interests: The authors have declared that no competing interests exist. Abbreviations: CC3, cleaved caspase 3; CCR2, C-C chemokine receptor 2; DBZ, dibenzazepine; IFN-c, interferon gamma; Ighm, Immunoglobulin heavy chain mu; ILCs, innate lymphoid cells; LV, latent variable; MAdCAM, mucosal addressin cell adhesion molecule 1; MCP-1, monocyte chemo-attractant protein 1; NK, natural killer; pDCs, plasmacytoid dendritic cells; PH3, phosphorylated histone H3; PLSDA, partial least squares discriminant analysis; Rag, Recombination activating gene; ROC, receiver operating characteristic; TCR, T cell receptor; Th, T helper; TNF-a, tumor necrosis factor alpha; Treg, T regulatory; WT, wild-type * E-mail: [email protected]