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The transcription factor MafB is expressed by monocytes and macrophages. Efferocytosis (apoptotic cell uptake) by macrophages is important for inhibiting the development of autoimmune diseases, and is greatly reduced in Mafb-deficient macrophages. Here, we show the expression of the first protein in the classical complement pathway C1q is important for mediating efferocytosis and is reduced in Mafb-deficient macrophages. The efferocytosis defect in Mafb-deficient macrophages can be rescued by adding serum from wild-type mice, but not by adding serum from C1q-deficient mice. By hemolysis assay we also show that activation of the classical complement pathway is decreased in Mafb-deficient mice. In addition, MafB overexpression induces C1q-dependent gene expression and signals that induce C1q genes are less effective in the absence of MafB. We also show that Mafb-deficiency can increase glomerular autoimmunity, including anti-nuclear antibody deposition. These results show that MafB is an important regulator of C1q.

Spaceflight causes a decrease in skeletal muscle mass and strength. We set two murine experimental groups in orbit for 35 days aboard the International Space Station, under artificial earth-gravity (artificial 1 g ; AG) and microgravity (μ g ; MG), to investigate whether artificial 1 g exposure prevents muscle atrophy at the molecular level. Our main findings indicated that AG onboard environment prevented changes under microgravity in soleus muscle not only in muscle mass and fiber type composition but also in the alteration of gene expression profiles. In particular, transcriptome analysis suggested that AG condition could prevent the alterations of some atrophy-related genes. We further screened novel candidate genes to reveal the muscle atrophy mechanism from these gene expression profiles. We suggest the potential role of Cacng1 in the atrophy of myotubes using in vitro and in vivo gene transductions. This critical project may accelerate the elucidation of muscle atrophy mechanisms.

MAFB is a basic leucine zipper (bZIP) transcription factor specifically expressed in macrophages. We have previously identified MAFB as a candidate marker for tumor-associated macrophages (TAMs) in human and mouse models. Here, we analyzed single-cell sequencing data of patients with lung adenocarcinoma obtained from the GEO database (GSE131907). Analyzed data showed that general macrophage marker CD68 and macrophage scavenger receptor 1 (CD204) were expressed in TAM and lung tissue macrophage clusters, while transcription factor MAFB was expressed specifically in TAM clusters. Clinical records of 120 patients with lung adenocarcinoma stage I (n = 57), II (n = 21), and III (n = 42) were retrieved from Tsukuba Human Tissue Biobank Center (THB) in the University of Tsukuba Hospital, Japan. Tumor tissues from these patients were extracted and stained with anti-human MAFB antibody, and then MAFB-positive cells relative to the tissue area (MAFB+ cells/tissue area) were morphometrically quantified. Our results indicated that higher numbers of MAFB+ cells significantly correlated to increased local lymph node metastasis (nodal involvement), high recurrence rate, poor pathological stage, increased lymphatic permeation, higher vascular invasion, and pleural infiltration. Moreover, increased amounts of MAFB+ cells were related to poor overall survival and disease-free survival, especially in smokers. These data indicate that MAFB may be a suitable prognostic biomarker for smoker lung cancer patients.

Long-duration spaceflight creates a variety of stresses due to the unique environment, which can lead to compromised functioning of the skeletal and immune systems. However, the mechanisms by which organisms respond to this stress remain unclear. The present study aimed to investigate the impact of three different gravitational loadings (microgravity, 1/6  g [lunar gravity], and 1  g ) on the behavior, bone, thymus, and spleen of mice housed for 25–35 days in the International Space Station. The bone density reduction under microgravity was mostly recovered by 1  g but only partially recovered by 1/6  g . Both 1  g and 1/6  g suppressed microgravity-induced changes in some osteoblast and osteoclast marker gene expression. Thymus atrophy induced by microgravity was half recovered by both 1  g and 1/6  g , but gene expression changes were not fully recovered by 1/6  g . While no histological changes were observed due to low gravity, alterations in gene expression were noted in the spleen. We found that in bone and thymus, lunar gravity reduced microgravity-induced histological alterations and partially reversed gene expression changes. This study highlighted organ-specific variations in responsiveness to gravity, serving as an animal test for establishing a molecular-level gravity threshold for maintaining a healthy state during future spaceflight.

This Japan Aerospace Exploration Agency project focused on elucidating the impacts of partial gravity (partial g ) and microgravity (μ g ) on mice using newly developed mouse habitat cage units (HCU) that can be installed in the Centrifuge-equipped Biological Experiment Facility in the International Space Station. In the first mission, 12 C57BL/6 J male mice were housed under μ g or artificial earth-gravity (1  g ). Mouse activity was monitored daily via downlinked videos; μ g mice floated inside the HCU, whereas artificial 1  g mice were on their feet on the floor. After 35 days of habitation, all mice were returned to the Earth and processed. Significant decreases were evident in femur bone density and the soleus/gastrocnemius muscle weights of μ g mice, whereas artificial 1  g mice maintained the same bone density and muscle weight as mice in the ground control experiment, in which housing conditions in the flight experiment were replicated. These data indicate that these changes were particularly because of gravity. They also present the first evidence that the addition of gravity can prevent decreases in bone density and muscle mass, and that the new platform ‘MARS’ may provide novel insights on the molecular-mechanisms regulating biological processes controlled by partial g /μ g .

Although an increased expression of the transcription factor v-maf avian musculoaponeurotic fibrosarcoma oncogene homolog B (MAFB) has been reported in patients with active tuberculosis (TB), its potential role in Mycobacterium tuberculosis infection remains unknown. Herein, we report that MafB in macrophages is a regulator of the pro-inflammatory cytokines, TNF-α and IL-12p40, which are crucial for host defense against M. tuberculosis infection. Cell-based luciferase assays showed that MafB inhibited TNF-α and IL-12p40 transcriptional activity in a dose-dependent manner. At the molecular level, MafB interacted with IFN regulatory factor (IRF)-5 and PU.1 and inhibited IRF-5- and PU.1-mediated transactivation, via the basic-leucine zipper domain. Analysis using gene-deficient macrophages demonstrated that the suppressed pro-inflammatory cytokine production during M. tuberculosis infection depends on MafB expression. Finally, in vivo studies indicated that M. tuberculosis -mediated increase of MafB expression was responsible for the exacerbation of M. tuberculosis infection. Thus, our results provide a functional view of MafB as a cytokine regulator as well as novel insights into host factors involved in TB susceptibility.

Non-alcoholic fatty liver disease (NAFLD) constitutes a metabolic disorder with high worldwide prevalence and increasing incidence. The inflammatory progressive state, non-alcoholic steatohepatitis (NASH), leads to liver fibrosis and carcinogenesis. Here, we evaluated whether tyrosinase mutation underlies NASH pathophysiology. Tyrosinase point-mutated B6 (Cg)- Tyr c-2J /J mice (B6 albino) and C57BL/6J black mice (B6 black) were fed with high cholesterol diet (HCD) for 10 weeks. Normal diet-fed mice served as controls. HCD-fed B6 albino exhibited high NASH susceptibility compared to B6 black, a phenotype not previously reported. Liver injury occurred in approximately 50% of B6 albino from one post HCD feeding, with elevated serum alanine aminotransferase and aspartate aminotransferase levels. NASH was induced following 2 weeks in severe-phenotypic B6 albino (sB6), but B6 black exhibited no symptoms, even after 10 weeks. HCD-fed sB6 albino showed significantly higher mortality rate. Histological analysis of the liver revealed significant inflammatory cell and lipid infiltration and severe fibrosis. Serum lipoprotein analysis revealed significantly higher chylomicron and very low-density lipoprotein levels in sB6 albino. Moreover, significantly higher small intestinal lipid absorption and lower fecal lipid excretion occurred together with elevated intestinal NPC1L1 expression. As the tyrosinase point mutation represents the only genetic difference between B6 albino and B6 black, our work will facilitate the identification of susceptible genetic factors for NASH development and expand the understanding of NASH pathophysiology.

MAFB, a transcription factor of the large Maf family, is expressed in both fetal liver (FL) and bone marrow (BM) hematopoietic stem cells (HSCs). However, its stage-specific roles remain elusive. Here, we reveal that MAFB plays distinct roles in FL and BM HSCs. Using Mafb -deficient and Mafb -GFP knock-in mouse models, we demonstrate that Mafb deletion enhances proliferation, cell cycle entry, and myeloid differentiation of FL HSCs, leading to enhanced chimerism rate in transplantation assays. However, Mafb -deficient BM HSCs exhibit impaired long-term reconstitution and progressive exhaustion, supported by serial transplantation and reduced colony-forming capacity. HSCs from Mafb f/f :: Tie2 -Cre mouse ( Mafb cKO) further revealed a significant decline in long-term HSC (LT-HSC) populations and multilineage differentiation potential. Together, our findings suggest a stage-dependent role of MAFB as a regulator of HSC proliferation during fetal development and a critical factor for HSC maintenance during adulthood, providing insights into the stage-specific regulation of HSC function linked to cell cycle control and long-term repopulation capacity.

In order to increase the contribution of donor HSC cells, irradiation and DNA alkylating agents have been commonly used as experimental methods to eliminate HSCs for adult mice. But a technique of HSC deletion for mouse embryo for increase contribution of donor cells has not been published. Here, we established for the first time a procedure for placental HSC transplantation into E11.5 Runx1 -deficient mice mated with G1-HRD-Runx1 transgenic mice ( Runx1 -/- ::Tg mice) that have no HSCs in the fetal liver. Following the transplantation of fetal liver cells from mice (allogeneic) or rats (xenogeneic), high donor cell chimerism was observed in Runx1 -/- ::Tg embryos. Furthermore, chimerism analysis and colony assay data showed that donor fetal liver hematopoietic cells contributed to both white blood cells and red blood cells. Moreover, secondary transplantation into adult recipient mice indicated that the HSCs in rescued Runx1 -/- ::Tg embryos had normal abilities. These results suggest that mice lacking fetal liver HSCs are a powerful tool for hematopoiesis reconstruction during the embryonic stage and can potentially be used in basic research on HSCs or xenograft models.

BACKGROUND: It is unclear whether the development of the branches of the subclavian artery is dependent on the proximal part of this artery, since great vessel formation is partly regulated by haemodynamic stress. For example, the vertebral artery that usually arises from the subclavian artery might be affected by anomalies in the aortic arch branches. This uncertainty is partly due to the limited reports of highly anomalous cases of proximal and distal branching morphologies. Here, we report the case of an Adachi-Williams type CG plus H aortic arch found during dissection, and discuss the development of the cervicothoracic circulation. CASE REPORT: We report an aberrant right subclavian artery that arose from the aorta distal to the left subclavian artery, via a retroesophageal course, whereas the right and left common carotid arteries arose from a short common trunk from the aorta (the carotid trunk) (Adachi-Williams type H). In addition, the left vertebral artery arose directly from the aortic arch between the carotid trunk and the left subclavian artery (Adachi-Williams type CG). Anomalies in the branching arteries from this aberrant right subclavian artery (the right vertebral artery, internal thoracic artery, thyrocervical trunk, costocervical trunk and thoracoacromial artery) were unidentifiable. The right vagus nerve directly innervates the laryngeal muscles without forming the recurrent nerve. CONCLUSIONS: The development of an aberrant right subclavian artery might affect haemodynamic stress in both the proximal and distal regions of the anterior limb region. The distal branching morphology, however, was normal, suggesting independence from proximal and distal vasculature development. Since the concomitance of Adachi-Williams types CG and H is rare, rather than sequentially develop, the distal arteries develop in a fine-tuned manner to adapt to anomalies in the proximal arteries.