Abstract
Cytosolic DNA sensing is a fundamental mechanism by which organisms handle various stresses, including infection and genotoxicity. The hematopoietic system is sensitive to stresses, and hematopoietic changes are often rapid and the first response to stresses. Based on the transcriptome database, cytosolic DNA sensing pathways are widely expressed in the hematopoietic system, and components of these pathways may be expressed at even higher levels in hematopoietic stem and progenitor cells (HSPCs) than in their certain progeny immune cells. Recent studies have described a previously unrecognized role for cytosolic DNA sensing pathways in the regulation of hematopoiesis under both homeostatic and stress conditions. In particular, the recently discovered cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) pathway is a critical modulator of hematopoiesis. Perturbation of the cGAS-STING pathway in HSPCs may be involved in the pathogenesis of hematopoietic disorders, autoimmune diseases, and inflammation-related diseases and may be candidate therapeutic targets. In this review, we focus on the recent findings of the cGAS-STING pathway in the regulation of hematopoiesis, and its physiopathological significance including its implications in diseases and therapeutic potential.
Highlights
Hematopoietic stem and progenitor cells (HSPCs) in the bone marrow (BM) are responsible for the maintenance of both the homeostatic and stressed hematopoiesis
We focus on the recent findings of the cyclic granulocyte-monocyte progenitors (GMPs)-AMP synthase (cGAS)-stimulator of interferon genes (STING) pathway in the regulation of hematopoiesis, and its physiopathological significance including its implications in diseases and therapeutic potential
The immunomodulatory effects of the cGAS-STING pathway in hematopoietic cells have been extensively studies, little attention has been paid to its roles in hematopoiesis
Summary
Hematopoietic stem and progenitor cells (HSPCs) in the bone marrow (BM) are responsible for the maintenance of both the homeostatic and stressed hematopoiesis. The ligated TLR9 interacts with its proximal adaptor protein, myeloid differentiation primary response 88 (MyD88), to activate TRAF6 and MAPKs [41]; activated AIM2 associates with the adaptor molecule apoptosis-associated speck-like protein containing caspase recruitment domain (ASC), to form an inflammasome complex, which activates gasdermin D (GSDMD)-mediated pyroptosis and caspase 1 (CASP1)-dependent maturation of interleukin 1b (IL1b) (Figure 1) [40, 42] Both TLR9 and AIM2 are dispensable for IFN-I induction, suggesting a central role of the cGAS-STING pathway in cytosolic DNA sensing. Upon stresses, such as infections and genotoxicity, a considerable number of hematopoietic cells, especially myeloid cells, are depleted. IFN-I signaling increases the phosphorylation of STAT1 and Akt/mTOR and upregulates the TABLE 1 | Roles of stress-related pathways including the cGAS-STING pathway in regulating HSPC maintenance
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