Usp22 is an intracellular regulator of systemic emergency hematopoiesis

Abstract

Emergency hematopoiesis is a concerted response aimed toward enhanced protection from infection, involving multiple cell types and developmental stages across the immune system. Despite its importance, the underlying molecular regulation remains poorly understood. The deubiquitinase USP22 regulates the levels of monoubiquitinated histone H2B (H2Bub1), which is associated with activation of interferon responses upon viral infection. Here, we show that in the absence of infection or inflammation, mice lacking Usp22 in all hematopoietic cells display profound systemic emergency hematopoiesis, evident by increased hematopoietic stem cell proliferation, myeloid bias, and extramedullary hematopoiesis. Functionally, loss of Usp22 results in elevated phagocytosis by neutrophilic granulocytes and enhanced innate protection against Listeria monocytogenes infection. At the molecular level, we found this state of emergency hematopoiesis associated with transcriptional signatures of myeloid priming, enhanced mitochondrial respiration, and innate and adaptive immunity and inflammation. Augmented expression of many inflammatory genes was linked to elevated locus-specific H2Bub1 levels. Collectively, these results demonstrate the existence of a tunable epigenetic state that promotes systemic emergency hematopoiesis in a cell-autonomous manner to enhance innate protection, identifying potential paths toward immune enhancement. Loss of Usp22 elicits a cellular and molecular program of emergency hematopoiesis and enhances innate protection in vivo. Hematopoietic state of emergency To support increased demands on the immune system in response to infection or inflammation, activation of emergency hematopoiesis stimulates hematopoietic stem cell (HSC) proliferation and myeloid-biased differentiation. Whereas pathogen recognition or inflammatory cytokines are typically involved in initiating this process, Dietlein et al. found that mice lacking the deubiquitinase USP22 in hematopoietic cells spontaneously adopt a state of emergency hematopoiesis in the absence of an infection. H2B monoubiquitination, an activating histone modification, was increased at interferon-stimulated gene (ISG) loci, corresponding to increased ISG expression in USP22-deficient HSCs. USP22-deficient mice were protected against bacterial infection, demonstrating that USP22 cell-intrinsically restrains hematopoietic responses that confer innate immune protection against pathogens.