ABSTRACT
Somatic mutation in TET2 gene is one of the most common clonal genetic events detected in age-related clonal hematopoiesis as well as in chronic myelomonocytic leukemia (CMML). In addition to being a pre-malignant state, TET2 mutated clones are associated with an increased risk of death from cardiovascular disease, which could involve cytokine/chemokine overproduction by monocytic cells. Here, we show in mice and in human cells that, in the absence of any inflammatory challenge, TET2 downregulation promotes the production of MIF (macrophage migration inhibitory factor), a pivotal mediator of atherosclerotic lesion formation. In healthy monocytes, TET2 is recruited to MIF promoter and interacts with the transcription factor EGR1 and histone deacetylases. Disruption of these interactions as a consequence of TET2-decreased expression favors EGR1-driven transcription of MIF gene and its secretion. MIF favors monocytic differentiation of myeloid progenitors. These results designate MIF as a chronically overproduced chemokine and a potential therapeutic target in patients with clonal TET2 downregulation in myeloid cells.
Subject(s)
DNA-Binding Proteins/metabolism , Dioxygenases/metabolism , Early Growth Response Protein 1/metabolism , Macrophage Migration-Inhibitory Factors/metabolism , Monocytes/metabolism , Animals , Cell Line , Cytokines/genetics , Cytokines/metabolism , DNA-Binding Proteins/genetics , Dioxygenases/genetics , Early Growth Response Protein 1/genetics , Gene Expression Regulation/physiology , Humans , Infant, Newborn , Macrophage Migration-Inhibitory Factors/genetics , MiceABSTRACT
BACKGROUND: Effective vaccines against porcine reproductive and respiratory syndrome virus (PRRSV), especially against highly pathogenic (HP) PRRSV are still missing. The objective of this study was to evaluate the protective efficacy of an experimental live attenuated PRRSV 2 vaccine, composed of two strains, against heterologous challenge with a Vietnamese HP PRRSV 2 field strain. For this reason, 20 PRRSV negative piglets were divided into two groups. The pigs of group 1 were vaccinated with the experimental vaccine, group 2 remained unvaccinated. All study piglets received an intranasal challenge of the HP PRRSV 2 on day 0 of the study (42 days after vaccination). Blood samples were taken on days 7 and 21 after vaccination and on several days after challenge. On day 28 after challenge, all piglets were euthanized and pathologically examined. RESULTS: On days 7 and 21 after vaccination, a PRRSV 2 viraemia was seen in all piglets of group 1 which remained detectable in seven piglets up to 42 days after vaccination. On day 3 after challenge, all piglets from both groups were positive in PRRSV 2 RT-qPCR. From day 7 onwards, viral load and number of PRRSV 2 positive pigs were lower in group 1 than in group 2. All pigs of group 1 seroconverted after PRRSV 2 vaccination. PRRSV antibodies were detected in serum of all study pigs from both groups from day 14 after challenge onwards. In group 2, moderate respiratory symptoms with occasional coughing were seen following the challenge with HP PRRSV 2. Pigs of group 1 remained clinically unaffected. Interstitial pneumonia was found in four piglets of group 1 and in all ten piglets of group 2. Histopathological findings were more severe in group 2. CONCLUSIONS: It was thus concluded that the used PRRSV 2 live experimental vaccine provided protection from clinical disease and marked reduction of histopathological findings and viral load in pigs challenged with a Vietnamese HP PRRSV 2 field strain.
