miR-146a – Traf6 regulatory axis controls autoimmunity and myelopoiesis, but is dispensable for hematopoietic stem cell homeostasis and tumor suppression

Abstract

microRNA-146a (miR-146a) has been previously implicated as an essential molecular brake, preventing immune overreaction and malignant transformation by attenuating NF-κB signaling, putatively via repression of the Traf6 and Irak1 genes. The exact contribution of miR-146a–mediated silencing of these genes to the control of immune activation is currently unknown. Therefore, we defined the role of the miR-146a–Traf6 signaling axis in the regulation of immune homeostasis using a genetic epistasis analysis in miR-146a−/− mice. We have uncovered a surprising separation of functions at the level of miR-146a targets. Lowering the Traf6 gene dose and consequent attenuation of NF-κB activation rescued several significant miR-146a−/− phenotypes, such as splenomegaly, aberrant myeloproliferation, and excessive inflammatory responses. In contrast, decreasing Traf6 expression had no effect on the development of the progressive bone marrow failure phenotype, as well as lymphomagenesis in miR-146a−/− mice, indicating that miR-146a controls these biological processes through different molecular mechanisms.

MiR-146a Deletion Protects From Bone Loss in OVX Mice by Suppressing RANKL/OPG and M-CSF in Bone Microenvironment

“…Some studies reported that miR‐146a knockout mice display the autoimmune‐like disease and cancer in aging period . In our study, we found that the bone mass of miR‐146a −/− ‐OVX mice was higher than that of WT‐OVX mice, which is consistent with the bone marrow myelofibrosis in old miR‐146a −/− mice . In addition, we found excessive trabecular bone in old female but not male miR‐146a −/− mice, which implied the combined effects of miR‐146a and estrogen on bone loss.…”

“…MiR‐146a is an important regulator of autoimmunity and inflammation by controlling the activation and transformation of immune cells . MiR‐146a directly targets to TNF receptor‐associated factor 6 (TRAF6) and IL‐1 receptor‐associated kinase 1 (IRAK1) and acts as an important regulator of the innate immune signaling depending on NF‐κB pathway . Some studies reported that miR‐146a knockout mice display the autoimmune‐like disease and cancer in aging period .…”

“…MiR‐146a has been reported related to autoimmunity, cancer, and myeloid malignancies . Many studies focused on the function of miR‐146a on rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), breast cancer, prostate cancer, myeloid leukemia, and myelodysplastic syndrome (MDS) . It has been shown that miR‐146a influences the development of rheumatoid arthritis by OC and synovium fibroblasts .…”

miR‐146a‐5p: Expression, regulation, and functions in cancer

“…This group published two follow-up studies with similar results Zhao, Rao, O'Connell, Garcia-Flores, & Baltimore, 2013). A more recent work found that TNF receptor associated factor 6 (TRAF6) expression is dispensable in miR-146a's tumor suppressive function in these cells (Magilnick et al, 2017). Chronic myeloid leukemia (CML) is a type of myeloid malignancy that is characterized by the presence of the Philadelphia chromosome, a translocation leading to activation of the fusion gene BCR-ABL.…”

“…Combination treatment of cells with curcumin and the cancer drug temozolomide inhibited proliferation and induced apoptosis greater than with temozolomide alone, but repeating this experiment in the presence of a miR-146a inhibitor prevented this enhancement. Repressed NF-κB signaling is key to miR- Promotes NF-κB signaling Hu et al (2018), Liu, Yi, et al (2015), , Hung et al (2013), Chen et al (2013), Kogo, Mimori, Tanaka, Komune, and Mori (2011), Li et al (2010aLi et al ( , 2010b, Bhaumik et al (2008) TRAF6 Cervical, Liver, Prostate, Breast, Oral, NK/T-cell lymphoma Promotes NF-κB signaling Hu et al (2018), Magilnick et al (2017), Zu et al (2016), Liu, Yi, et al (2015), , Hung et al (2013), Paik et al (2011), Bhaumik et al (2008 EGFR Penile, Breast, Pancreatic, Liver, Lung, Prostate, Gastric…”