PRJNA506145
ARTD1 in myeloid cells controls the IL-12/18-IFN-? axis in a model of sterile sepsis, chronic bacterial infection and cancer
Mice deficient for ADP-ribosyltransferase diphteriatoxin-like 1 (ARTD1) are protected against microbially induced inflammation. To address the contribution of ARTD1 to inflammation specifically in myeloid cells, we generated an Artd1?Myel mouse strain with conditional ARTD1 deficiency in myeloid lineages and examined the strain in three disease models. We found that ARTD1, but not its enzymatic activity, enhanced the transcriptional activation of distinct LPS-induced genes that included IL-12, TNF-a and IL-6 in primary bone-marrow derived macrophages and LPS-induced IL-12/IFN-? signaling in Artd1?Myel mice. The loss of Artd1 in myeloid cells also reduced the TH1 response to Helicobacter pylori and impaired immune control of the bacteria. Furthermore, Artd1?Myel mice failed to control tumor growth in a subcutaneous MC-38 model of colon cancer, which could be attributed to reduced TH1 and CD8 responses. Together, these data provide strong evidence for a cell-intrinsic role of ARTD1 in myeloid cells that is independent of its enzymatic activity and promotes type I immunity by promoting IL-12/18 expression.