Keep calm and IL-10, a story of gut and brain macrophages

The recent past has seen major advances in our understanding of macrophage contributions to physiology and pathophysiology. Intra-vital imaging, fate mapping, cell ablation and targeted mutagenesis in mouse models, complemented by advanced transcriptome, translatome, and epigenome profiling have provided insights of unprecedented depth. Collectively, these studies highlight that macrophages need to be studied in physiological context since their identities and functions are defined by the local tissue environment. Here I will discuss our efforts to probe tissue macrophages in gut and CNS. Specifically, we focus on the IL10 / IL10 receptor axis and its critical role in ensuring macrophage quiescence following respective physiological environmental challenge in the intestine and the brain.eed

In the colon, macrophages are critical for gut homeostasis. In a murine IBD model based on a macrophage-restricted Interleukin 10 (IL-10) receptor deficiency, pro-inflammatory mutant gut macrophages cause severe spontaneous colitis resembling the condition of children carrying IL10R mutations (Zigmond et al., 2014). We now established that macrophage-derived IL-23 is the driving factor of this pathology. Specifically, we report that Cx3cr1^Cre: Il10ra^fl/fl:Il23a^fl/fl mice harboring macrophages deficient for both IL-10R and IL-23 are protected from colitis (Bernshtein et al., SI 2019). Furthermore, by analyzing the epithelial response to pro-inflammatory macrophages, we provide evidence that T cells of colitic animals produce deleterious IL-22 that induces epithelial chemokine expression and detrimental neutrophil recruitment. Collectively, this defines critical cell-type-specific contributions to the induction and effector mechanism of macrophage-driven colitis, as manifested in mice harboring IL-10R deficiencies and human IBD pathologies.

Also all microglia, the parenchymal brain macrophages, prominently express IL10 receptor. However, analysis of Tamoxifen-treated Cx3cr1^CreER: Il10ra^fl/fl mice suggests that IL-10 sensing is dispensable to maintain brain homeostasis (Shemer et al. in preparation). Rather, we will report data establishing that IL-10 is required to rapidly and robustly restore microglia quiescence following peripheral endotoxin challenge.