Figure 3.
1: ADA2 as an extracellular deaminase. NETosis increases A1R/A3R, which raises IL-6, IL-8, and TNF-alpha. ADA2 secretion increases adenosine and deoxyadenosine while preventing inosine and deoxyinosine formation. This affects M1 and M2 macrophages, raising IL-6, IL-8, and TNF-alpha. A2BR activation raises tnfa, il1b, and il6. dIno converts to SAM, which affects ERV and raises Type I IFN. 2: ADA2 as a lysosomal enzyme. ADA2 prevents deoxyadenosine formation, affecting TLR9 and Type I IFN production in pDCs. Without ADA2, deoxyinosine affects TLR9, increasing Type I IFN.
Proposed DADA2 pathomechanisms focusing on ADA2 as an extracellular adenosine deaminase or as a lysosomal protein (1, 97, 111, 112, 113, 114, 115, 116). Ado, adenosine; dAdo, deoxyadenosine; dIno, deoxyinosine; ERV, endogenous retroviral elements; HSC, hematopoietic stem cell; HUVECs, human umbilical vein endothelial cells; Ino, inosine; NET, neutrophil extracellular traps; SAM, s-adenosyl methionine.