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Several cytokines maintain intestinal health, but precise inter-cellular communication networks remain poorly understood. Macrophages are immune sentinels of the intestinal tissue, critical for gut homeostasis. Here we show that in a murine IBD model based on macrophage-restricted Interleukin 10 (IL-10) receptor deficiency (Cx3cr1Cre:Il10rafl/fl mice), pro-inflammatory mutant gut macrophages cause severe spontaneous colitis resembling the condition of children carrying IL10R mutations. We establish macrophage-derived IL-23 as the driving factor of this pathology. Specifically, we report that Cx3cr1Cre: Il10rafl/fl:Il23afl/fl mice harboring macrophages deficient for both IL-10R and IL-23 are protected from colitis. 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, we define 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.

Conditional mutagenesis and fate mapping have contributed considerably to our understanding of physiology and pathology. Specifically, Cre recombinase‐based approaches allow the definition of cell type‐specific contributions to disease development and of inter‐cellular communication circuits in respective animal models. Here we compared Cx3cr1CreER and Sall1CreER transgenic mice and their use to decipher the brain macrophage compartment as a showcase to discuss recent technological advances. Specifically, we highlight the need to define the accuracy of Cre recombinase expression, as well as strengths and pitfalls of these particular systems that should be taken into consideration when applying these models.

Background: TOR complex 2 (TORC2) is a conserved protein complex that regulates multiple aspects of cell survival and proliferation. Results: DNA metabolism and DNA damage response are impaired upon disruption of TORC2. Conclusion: TORC2 affects replication-associated damages, independent of checkpoint activation. Significance: TORC2 is required to maintain genome stability in fission yeast, a function that may be evolutionarily conserved.

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