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.
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.
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.
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 inter-cellular communication circuits in respective animals models. Here we compared Cx 3 cr1 CreER and Sall1 CreER 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.
The small intestine hosts specialized lymphoid structures, the Peyer's patches, that face the gut lumen and are overlaid with unique epithelial cells, called microfold (M) cells. M cells are considered to constitute an important route for antigen uptake in the mucosal immune system. Here, we used intravital microscopy to define immune cell populations, which are in close contact with M cells and potentially sample antigen. We present live evidence that DCs enter M cell pockets and highlight the abundance of mononuclear phagocytes in these structures. Taking advantage of the respective reporter animals, we focused on classical DCs that express Zbtb46 and analyzed how these cells interact with M cells in steady state and sample antigen for T cell activation in the Peyer's patches following challenge.
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