The cGAS-STING pathway promotes acute ischemia-induced neutropoiesis and neutrophil priming in the bone marrow.

Our previous work demonstrated that the DNA-sensing receptor cyclic GMP-AMP synthase (cGAS) negatively affects post-infarct repair by promoting pro-inflammatory macrophages. However, whether cGAS and its downstream partner STING (Stimulator of Interferon Genes) regulate neutrophil production and function in the context of acute myocardial ischemia remains unclear. This study investigated the role of the cGAS-STING pathway in neutropoiesis (neutrophil production and differentiation) and examined whether ischemia primes neutrophils in the bone marrow via this pathway, enhancing their functionality and contributing to cardiac inflammatory injury. Using myocardial infarction (MI) models in wild-type (WT), Cgas-/-, and Sting-/- mice, we analyzed neutrophils from the bone marrow, peripheral blood, and infarcted tissue. Additionally, we generated neutrophil-specific conditional knockouts of Cgas and performed adoptive transfer experiments with Cgas-deficient neutrophils. RNA sequencing revealed that ischemia increased neutrophil production in the bone marrow and activated pathways involved in cytokine signaling, phagocytosis, chemotaxis, and degranulation. Inhibiting the cGAS-STING pathway reduced neutrophil production by decreasing lineage committed neutrophil precursors including early neutrophil precursors (eNP) and preNeu and downregulated ischemia-induced pathways. Neutrophil conditional Cgas deletion or adoptive transfer of Cgas-deficient neutrophils improved survival but did not significantly impact ischemia-induced remodeling. In conclusion, we demonstrate for the first time that ischemia enhanced neutrophil functionality before recruitment to infarcted tissue, and the cGAS-STING pathway played an important role in neutrophil production and priming. Furthermore, our findings demonstrate a neutrophil-specific role of cGAS in promoting cardiac rupture and mortality in MI. This study provides a more comprehensive understanding of the cGAS-STING pathway in acute ischemia and may support the translation of cGAS-STING modulators, an emerging therapeutic field.