Studying Communication Circuits of Intestinal Macrophages and Their Environment in the Healthy and Inflamed Gut

Intestinal macrophages reside in the connective tissue underlying the gut epithelium, which separates them from the diverse microbiota populating the gut lumen. This complex and dynamic environment necessitates intimate and precise inter-cellular communication. Unlike other tissue macrophages, gut macrophages derive from monocytes, most likely recruited by tonic low-grade inflammatory stimuli. Upon arrival in healthy gut tissue, monocytes adopt a non-inflammatory fate that is critical for maintenance of gut homeostasis¹. 

We recently established a murine colitis model by taking advantage of CX3CR1-Cre animals² to generate mice that harbor macrophage-restricted Interleukin 10 receptor (IL10R) deficiency. IL10R-deficient gut macrophages are pro-inflammatory, causing severe, early onset colitis that resembles the pathology of children carrying IL10R mutations³.

To investigate how macrophage dysregulation affects the epithelium, we performed RNAseq of small and large intestinal epithelial cells of mice harboring IL10R-deficient macrophages. Epithelial cells readily respond to pro-inflammatory macrophages by up-regulation of anti-microbial peptide secretion, and alterations in their differentiation program. To further dissect the specific communication modules between macrophages and epithelial cells, we take advantage of cell ablation and reconstitution models developed in our lab⁴. By transferring IL10R-deficient and sufficient monocytes to mice ablated of mononuclear phagocytes, we are able to follow the differentiation steps of these cells while interacting with their close environment.

Bibliography: (1) Zigmond E. et al. Immunity 37, 2012; (2) Yona S. et al. Immunity 38, 2013; (3) Zigmond E, Bernshtein B et al. Immunity 40, 2014; (4) Varol C. et al. Immunity 31, 2009