Irgm1 protects hematopoietic stem cells by negative regulation of interferon signaling

The interferon-inducible immunity-related p47 GTPase Irgm1 has been linked to Crohn’s disease as well as susceptibility to tuberculosis. Previously we demonstrated that hematopoietic stem cell (HSC) quiescence and function are aberrant in mice lacking Irgm1 . To investigate the molecular basis for these defects, we conducted microarray expression profiling of Irgm1 -deficient HSCs. Cell cycle and interferon-response genes are upregulated in Irgm1 -/- HSCs, consistent with dysregulated interferon signaling. To test the hypothesis that Irgm1 normally downregulates interferon signaling in HSCs, we generated Irgm1 -/- Ifngr1 -/- and Irgm1 -/- Stat1 -/- double knock-out animals. Strikingly, hyperproliferation, self-renewal, and autophagy defects in Irgm1 -/- HSCs were rescued in double knock-out animals. These defects were also rescued in Irgm1 -/- Irgm3 -/- double knock-out animals, indicating that Irgm1 may regulate Irgm3 activity. Furthermore, the number of HSCs was reduced in aged Irgm1 -/- animals, suggesting that negative feedback inhibition of interferon signaling by Irgm1 is necessary to prevent hyperproliferation and depletion of the stem cell compartment. Collectively, our results indicate that Irgm1 is a powerful negative regulator of IFN-dependent stimulation in HSCs, with an essential role in preserving HSC number and function. The deleterious effects of excessive interferon signaling may explain how hematologic abnormalities arise in patients with inflammatory conditions. conditions, HSCs can be stimulated to divide and/or differentiate into all of the cell types of the peripheral blood 15 . Mice deficient in Irgm1 become anemic and neutropenic as a result of chronic infection, and their HSCs are strikingly defective in the ability to reconstitute the blood of a bone marrow-depleted host 14 . We sought to characterize the mechanism of Irgm1- dependent regulation of HSC proliferation and function, with the hopes that such knowledge might elucidate the pathophysiology of hematologic abnormalities associated with inflammatory conditions, including autoimmune diseases and chronic infections.

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