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J Immunol. 2019 Mar 1;202(5):1406-1416. doi: 10.4049/jimmunol.1801107. Epub 2019 Jan 23.

ARTD1 in Myeloid Cells Controls the IL-12/18-IFN-γ Axis in a Model of Sterile Sepsis, Chronic Bacterial Infection, and Cancer.

Author information

1
Department of Molecular Mechanisms of Disease, University of Zurich, 8057 Zurich, Switzerland.
2
Molecular Life Science Ph.D. Program of the Life Science Zurich Graduate School, 8057 Zurich, Switzerland.
3
Institute of Molecular Cancer Research, University of Zurich, 8057 Zurich, Switzerland.
4
Cancer Biology Ph.D. Program of the Life Science Zurich Graduate School, 8057 Zurich, Switzerland.
5
Institute of Experimental Immunology, University of Zurich, 8057 Zurich, Switzerland; and.
6
Comprehensive Pneumology Center, Ludwig Maximilian University, University Hospital Grosshadern, and Helmholtz Center Munich, 81377 Munich, Germany.
7
Department of Molecular Mechanisms of Disease, University of Zurich, 8057 Zurich, Switzerland; michael.hottiger@dmmd.uzh.ch.

Abstract

Mice deficient for ADP-ribosyltransferase diphteria toxin-like 1 (ARTD1) are protected against microbially induced inflammation. To address the contribution of ARTD1 to inflammation specifically in myeloid cells, we generated an Artd1ΔMyel 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-α, and IL-6 in primary bone marrow-derived macrophages and LPS-induced IL-12/18-IFN-γ signaling in Artd1ΔMyel mice. The loss of Artd1 in myeloid cells also reduced the TH1 response to Helicobacter pylori and impaired immune control of the bacteria. Furthermore, Artd1ΔMyel mice failed to control tumor growth in a s.c. 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.

PMID:
30674576
DOI:
10.4049/jimmunol.1801107

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