Macrophage scavenger receptor-A1 promotes skeletal muscle regeneration after hindlimb ischemia.

Macrophages mediated inflammatory response is crucial for the recovery of skeletal muscle following ischemia. Thus, it's necessary to exploit macrophages based therapeutic targets for ischemic disease. Here, we found mRNA level of SR-A1 was elevated in patients with critical limb ischemia by analysis of gene expression omnibus (GEO) database. Then we investigated the role and the underlined mechanisms of macrophage SR-A1 in a mouse HLI model. Compared with the SR-A1 fl/fl mice, the Lyz Cre/+/SR-A1 flox/flox (SR-A1 ΔMΦ) mice showed significantly lower laser doppler blood flow in the ischemic limb at day 7 after HLI. Consistently, histological analysis exhibited that ischemic limb of SR-A1 ΔMΦ mice displayed more sever and sustained necrotic morphology, inflammation and fibrosis, decreased vessel density and regeneration rate, compared with which of control SR-A1 fl/fl mice. Furthermore, restoration of wild-type myeloid cells to SR-A1 knock-out mice effectively relieved the doppler perfusion in the ischemic limb and restrained skeletal muscle damage 7 days post HLI. In line with in vivo findings, when co-cultivating macrophages with the mouse myoblast line C2C12, SR-A1 -/- bone marrow macrophage significantly inhibited myoblast differentiation in vitro. Mechanically, SR-A1 enhanced skeletal muscle regeneration response to HLI by inhibiting the oncostatin M (OSM) production via suppressed NF-κB signaling activation. These results indicates that SR-A1 is a promising candidate molecule to improve tissue repair and regeneration in peripheral ischemic arterial disease.

Disruption of TIGAR-TAK1 alleviates immunopathology in a murine model of sepsis.

Macrophage-orchestrated inflammation contributes to multiple diseases including sepsis. However, the underlying mechanisms remain to be defined clearly. Here, we show that macrophage TP53-induced glycolysis and apoptosis regulator (TIGAR) is up-regulated in murine sepsis models. When myeloid Tigar is ablated, sepsis induced by either lipopolysaccharide treatment or cecal ligation puncture in male mice is attenuated via inflammation inhibition. Mechanistic characterizations indicate that TIGAR directly binds to transforming growth factor ß-activated kinase (TAK1) and promotes tumor necrosis factor receptor-associated factor 6-mediated ubiquitination and auto-phosphorylation of TAK1, in which residues 152-161 of TIGAR constitute crucial motif independent of its phosphatase activity. Interference with the binding of TIGAR to TAK1 by 5Z-7-oxozeaenol exhibits therapeutic effects in male murine model of sepsis. These findings demonstrate a non-canonical function of macrophage TIGAR in promoting inflammation, and confer a potential therapeutic target for sepsis by disruption of TIGAR-TAK1 interaction.

Major vault protein (MVP) suppresses aging- and estrogen deficiency-related bone loss through Fas-mediated apoptosis in osteoclasts.

Osteoclasts (OCs), derived from monocyte/macrophage lineage, are key orchestrators in bone remodeling. Targeting osteoclast apoptosis is a promising approach to cut down excessive osteoclast numbers, and thus slow down the rate of bone mass loss that inevitably occurs during aging. However, the therapeutic target of apoptosis in osteoclasts has not been fully studied. Our previous work generated Mvpf/fLyz2-Cre mice, conditionally depleting major vault protein (MVP) in monocyte lineage, and identified MVP as a bone protector for its negative role in osteoclastogenesis in vivo and in vitro. Here, we observed a notable decline of MVP in osteoclasts with aging in mice, encouraging us to further investigate the regulatory role of osteoclast MVP. Then, Mvpf/fLyz2-Cre mice were exploited in two osteoporosis contexts, aging and abrupt loss of estrogen, and we revealed that conditional knockout of MVP inhibited osteoclast apoptosis in vivo and in vitro. Moreover, we reported the interaction between MVP and death receptor Fas, and MVP-Fas signaling cascade was identified to positively regulate the apoptosis of osteoclasts, thus preventing osteoporosis. Collectively, our comprehensive discovery of MVP's regulatory role in osteoclasts provides new insight into osteoclast biology and therapeutic targets for osteoporosis.

Macrophage MVP regulates fracture repair by promoting M2 polarization via JAK2-STAT6 pathway.

OBJECTIVE: Major vault protein (MVP) is vital in various macrophage-related inflammatory diseases. However, the effects of MVP on macrophage polarization during fracture repair are still unknown. METHODS: We used Mvpflox/floxLyz2-Cre mice (myeloid-specific MVP gene knockout, abbreviated as MacKO) and Mvpflox/flox (abbreviated as MacWT) mice to compare their fracture healing phenotype. Next, we traced the changes in macrophage immune status in vivo and in vitro. We further explored the effects of MVP on osteogenesis and osteoclastogenesis. Finally, we re-expressed MVP in MacKO mice to confirm the role of MVP in fracture healing. RESULTS: The lack of MVP in macrophages impaired their transition from a pro-inflammatory to an anti-inflammatory phenotype during fracture repair. The increased secretion of pro-inflammatory cytokines by macrophages promoted their osteoclastic differentiation and impaired BMSC osteogenic differentiation, ultimately leading to impaired fracture repair in MacKO mice. Last, adeno-associated virus (AAV)-Mvp tibial injection significantly promoted fracture repair in MacKO mice. CONCLUSIONS: Our findings showed MVP has a previously unknown immunomodulatory role in macrophages during fracture repair. Targeting macrophage MVP may represent a novel therapeutic method for fracture treatment.

Macrophage scavenger receptor A1 antagonizes abdominal aortic aneurysm via upregulating IRG1.

AIMS: Abdominal aortic aneurysm (AAA) is a common, usually asymptomatic disease with high mortality and limited therapeutic options. Extensive extracellular matrix (ECM) fragmentation and transmural inflammation act as major pathological processes of AAA. However, the underlying regulatory mechanisms remain incompletely understood. Herein, we aimed to investigate the role of scavenger receptor A1 (SR-A1), a key pattern recognition receptor modulating macrophage activity, in pathogenesis of AAA. METHODS AND RESULTS: The AAA model was generated by administration of angiotensin II (Ang II) into apolipoprotein E knockout mice or peri-arterial application of calcium phosphate in C57BJ/6L mice. We found that SR-A1 was markedly down-regulated in the macrophages isolated from murine AAA aortas. Global or myeloid-specific ablation of SR-A1 aggravated vascular inflammation, loss of vascular smooth muscle cells and degradation of the extracellular matrix. These effects of SR-A1 deficiency on AAA development were mediated by suppressed immunoresponsive gene 1 (IRG1) and increased inflammatory response in macrophages. Mechanically, binding of SR-A1 with Lyn led to STAT3 phosphorylation and translocation into the nucleus, in which STAT3 promoted IRG1 transcription through directly binding to its promoter. Restoration of macrophage SR-A1 in SR-A1-deficient mice by bone marrow transplantation or administration of 4-octyl itaconate, the derivate of IRG1 product itaconate, could relieve murine AAA. CONCLUSION: Our study reveals a protective effect of macrophage SR-A1-STAT3-IRG1 axis against aortic aneurysm formation via inhibiting inflammation.

Ferritin triggers neutrophil extracellular trap-mediated cytokine storm through Msr1 contributing to adult-onset Still's disease pathogenesis.

Hyperferritinemic syndrome, an overwhelming inflammatory condition, is characterized by high ferritin levels, systemic inflammation and multi-organ dysfunction, but the pathogenic role of ferritin remains largely unknown. Here we show in an animal model that ferritin administration leads to systemic and hepatic inflammation characterized by excessive neutrophil leukocyte infiltration and neutrophil extracellular trap (NET) formation in the liver tissue. Ferritin-induced NET formation depends on the expression of peptidylarginine deiminase 4 and neutrophil elastase and on reactive oxygen species production. Mechanistically, ferritin exposure increases both overall and cell surface expression of Msr1 on neutrophil leukocytes, and also acts as ligand to Msr1 to trigger the NET formation pathway. Depletion of neutrophil leukocytes or ablation of Msr1 protect mice from tissue damage and the hyperinflammatory response, which further confirms the role of Msr1 as ferritin receptor. The relevance of the animal model is underscored by the observation that enhanced NET formation, increased Msr1 expression and signalling on neutrophil leukocytes are also characteristic to adult-onset Still's disease (AOSD), a typical hyperferritinemic syndrome. Collectively, our findings demonstrate an essential role of ferritin in NET-mediated cytokine storm, and suggest that targeting NETs or Msr1 may benefit AOSD patients.

Major Vault Protein Prevents Atherosclerotic Plaque Destabilization by Suppressing Macrophage ASK1-JNK Signaling.

BACKGROUND: Macrophages are implicated in atherosclerotic plaque instability by inflammation and degradation of extracellular matrix. However, the regulatory mechanisms driving these macrophage-associated processes are not well understood. Here, we aimed to identify the plaque destabilization-associated cytokines and signaling pathways in macrophages. METHODS: The atherosclerotic models of myeloid-specific MVP (major vault protein) knockout mice and control mice were generated. Atherosclerotic instability, macrophage inflammatory signaling, and active cytokines released by macrophages were examined in vivo and in vitro by using cellular and molecular biological approaches. RESULTS: MVP deficiency in myeloid cells exacerbated murine plaque instability by increasing production of both MMP (matrix metallopeptidase)-9 and proinflammatory cytokines in artery wall. Mechanistically, expression of MMP-9 was mediated via ASK1 (apoptosis signal-regulating kinase 1)-MKK-4 (mitogen-activated protein kinase kinase 4)-JNK (c-Jun N-terminal kinase) signaling in macrophages. MVP and its α-helical domain could bind with ASK1 and inhibit its dimerization and phosphorylation. A 62 amino acid peptide (MVP-[686-747]) in the α-helical domain of MVP showed a crucial role in preventing macrophage MMP-9 production and plaque instability. CONCLUSIONS: MVP may act as an inhibitor for ASK1-JNK signaling-mediated MMP-9 production in macrophages and, thereby, attenuate unstable plaque formation. Our findings suggest that suppression of macrophage ASK1-JNK signaling may be a useful strategy antagonizing atherosclerotic diseases.

Serum amyloid A1 exacerbates hepatic steatosis via TLR4-mediated NF-κB signaling pathway.

OBJECTIVE: Chronic inflammatory response plays a prominent role in obesity-related nonalcoholic fatty liver disease (NAFLD). However, the intrahepatic triggering mechanism of inflammation remains obscure. This study aimed to elucidate the role of serum amyloid A1 (SAA1), an acute-phase response protein, in the obesity-induced hepatic inflammation and NAFLD. METHODS: Male mice were fed a high fat diet (HFD) for 16 weeks, and insulin resistance, hepatic steatosis, and inflammation in mice were monitored. Murine SAA1/2 was genetically manipulated to investigate the role of SAA1 in NAFLD. RESULTS: We found that SAA1 was increased in the NAFLD liver in both humans and mice. Knockout of SAA1/2 or knockdown of hepatic SAA1/2 promoted energy expenditure and alleviated HFD-induced metabolic disorder, hepatic steatosis, and inflammation. Endogenous overexpression of SAA1 in hepatocytes by adeno-associated virus 8 (AAV8) transfection aggravated overnutrition-associated gain of body weight, insulin resistance, hepatic lipid accumulation, and liver injury, which were markedly alleviated by knockout of murine toll-like receptor 4 (TLR4). Mechanistically, SAA1 directly bound with TLR4/myeloid differentiation 2 (MD2) to induce TLR4 internalization, leading to the activation of nuclear factor (NF)-κB signaling and production of both SAA1 and other inflammatory cytokines, including interleukin (IL)-6 and C-C chemokine ligand (CCL2) in hepatocytes. Administration of HFD mice with an AAV8-shRNA-SAA1/2 showed a therapeutic effect on hepatic inflammation and NAFLD progression. CONCLUSIONS: These results demonstrate that SAA1 triggers hepatic steatosis and intrahepatic inflammatory response by forming a SAA1/TLR4/NF-κB/SAA1 feedforward regulatory circuit, which, in turn, leads to NAFLD progression. SAA1 may act as a potential target for the disease intervention.

Major vault protein (MVP) negatively regulates osteoclastogenesis via calcineurin-NFATc1 pathway inhibition.

Rationale: Bone homeostasis is maintained by a balanced interplay of osteoblasts and osteoclasts. Osteoclasts are derived from monocyte/macrophage lineage. Major vault protein (MVP) is known to promote apoptosis and prevent metabolic diseases in macrophage. However, whether MVP is involved in osteoclastogenesis is unknown. Here, we identified an important function of MVP as a negative regulator of osteoclastogenesis and its therapeutic potential in preventing bone loss. Methods: Expression of MVP in osteoclasts was investigated in human tumor tissues with immunohistochemical staining. Next, we generated total body (Mvp-/- ) and monocyte-specific (Mvpf/fLyz2-Cre) MVP gene knockout mice to observe bone phenotype and osteoclastogenesis using micro-CT and bone histomorphometry. Moreover, we examined the effects of MVP on osteoclast differentiation, bone resorption, NFATc1 activation and calcium oscillations in vitro. Finally, we explored the clinical potential of targeting MVP in two osteoporosis mouse models and used an adeno-associated virus (AAV) gene to overexpress MVP locally in mice. Results: We found that Mvp-/- and Mvpf/fLyz2-Cre mice both exhibited osteoporosis-like phenotypes. MVP-deficiency also enhanced calcineurin-NFATc1 signaling and promoted NFATc1 activity, which led to enhanced osteoclastogenesis and bone resorption. Calcineurin inhibition using the small molecule inhibitor FK506 corrected the enhanced osteoclastogenesis in Mvpf/fLyz2-Cre group. Additionally, MVP reexpression in Mvpf/fLyz2-Cre group rescued calcineurin expression. MVP overexpression in wild-type mice prevented pathologic bone loss in mouse models of ovariectomized (OVX) and calvaria-adjacent lipopolysaccharide (LPS)-injected. Conclusions: Our data suggested that MVP negatively regulates osteoclast differentiation and bone resorption via inhibition of calcineurin-NFATc1 signaling. In osteoclast-related bone diseases such as osteoporosis, manipulation of MVP activity may be an attractive therapeutic target.

Trio cooperates with Myh9 to regulate neural crest-derived craniofacial development.

Trio is a unique member of the Rho-GEF family that has three catalytic domains and is vital for various cellular processes in both physiological and developmental settings. TRIO mutations in humans are involved in craniofacial abnormalities, in which patients present with mandibular retrusion. However, little is known about the molecular mechanisms of Trio in neural crest cell (NCC)-derived craniofacial development, and there is still a lack of direct evidence to assign a functional role to Trio in NCC-induced craniofacial abnormalities. Methods:In vivo, we used zebrafish and NCC-specific knockout mouse models to investigate the phenotype and dynamics of NCC development in Trio morphants. In vitro, iTRAQ, GST pull-down assays, and proximity ligation assay (PLA) were used to explore the role of Trio and its potential downstream mediators in NCC migration and differentiation. Results: In zebrafish and mouse models, disruption of Trio elicited a migration deficit and impaired the differentiation of NCC derivatives, leading to craniofacial growth deficiency and mandibular retrusion. Moreover, Trio positively regulated Myh9 expression and directly interacted with Myh9 to coregulate downstream cellular signaling in NCCs. We further demonstrated that disruption of Trio or Myh9 inhibited Rac1 and Cdc42 activity, specifically affecting the nuclear export of ß-catenin and NCC polarization. Remarkably, craniofacial abnormalities caused by trio deficiency in zebrafish could be partially rescued by the injection of mRNA encoding myh9, ca-Rac1, or ca-Cdc42. Conclusions: Here, we identified that Trio, interacting mostly with Myh9, acts as a key regulator of NCC migration and differentiation during craniofacial development. Our results indicate that trio morphant zebrafish and Wnt1-cre;Triofl/fl mice offer potential model systems to facilitate the study of the pathogenic mechanisms of Trio mutations causing craniofacial abnormalities.

Class A1 scavenger receptor prevents obesity-associated blood pressure elevation through suppressing overproduction of vascular endothelial growth factor B in macrophages.

AIMS: Dysfunctional innate immune function and inflammation contributes to the pathogenesis of obesity-associated hypertension, in which macrophage infiltration in the perivascular adipose tissue (PVAT) plays a key role. However, the mechanisms behind it are not well understood. Class A1 scavenger receptor (SR-A1) is one of the major pattern recognition receptors in modulating macrophage activity, and here, we aimed to investigate its role in obesity-associated hypertension. METHODS AND RESULTS: Both diet-induced and genetic obesity were generated in mice. Deficiency in SR-A1 aggravated the obesity-induced blood pressure (BP) elevation and endothelial dysfunction in mice. The BP-elevating effect of SR-A1 deficiency was blocked by the down-regulation of vascular endothelial growth factor B (VEGF-B) in obese mice. Overexpression of VEGF-B raised BP in the obese mice but not in normal mice. Administration of fucoidan, a ligand of SR-A1, lowered BP, and VEGF-B levels in Sr-a1+/+ but not in Sr-a1-/- obese mice. CONCLUSION: These results reveal a new link between PVAT and vascular biology in obesity orchestrated by the SR-A1/VEGF-B axis in macrophages. SR-A1 and VEGF-B may be promising therapeutic targets in the treatment of obesity-associated hypertension.

Effect of melatonin on regeneration of cortical neurons in rats with traumatic brain injury.

PURPOSE: To investigate the effect of melatonin on regeneration of cortical neurons in rats with traumatic brain injury (TBI). METHODS: Sprague-Dawley rats (n=36) were randomly divided into sham, TBI+vehicle and TBI+melatonin groups. Cerebral blood flow and cognitive function were observed via laser Doppler flowmetry and by Morris water maze testing, respectively. The serum malondialdehyde (MDA) and superoxide dismutase (SOD) levels were used to assess oxidative stress. Immunofluorescence and terminal deoxynucleotidyl transferase dUTP nick end labelling assay was used to observe the newborn neurons and apoptotic cells. RESULTS: Cerebral blood flow in the TBI+melatonin group was higher than that of the TBI+vehicle group at one, 12, 24 and 48 h post-injury, but the difference was not statistically significant (P>0.05). The cognitive function of the rats was better in the TBI+melatonin group than the TBI+vehicle group (P.

Self-Maintenance of Cardiac Resident Reparative Macrophages Attenuates Doxorubicin-Induced Cardiomyopathy Through the SR-A1-c-Myc Axis.

RATIONALE: Doxorubicin-induced cardiomyopathy (DiCM) is a primary cause of heart failure and mortality in cancer patients, in which macrophage-orchestrated inflammation serves as an essential pathological mechanism. However, the specific roles of tissue-resident and monocyte-derived macrophages in DiCM remain poorly understood. OBJECTIVE: Uncovering the origins, phenotypes, and functions of proliferative cardiac resident macrophages and mechanistic insights into the self-maintenance of cardiac macrophage during DiCM progression. METHODS AND RESULTS: Mice were administrated with doxorubicin to induce cardiomyopathy. Dynamic changes of resident and monocyte-derived macrophages were examined by lineage tracing, parabiosis, and bone marrow transplantation. We found that the monocyte-derived macrophages primarily exhibited a proinflammatory phenotype that dominated the whole DiCM pathological process and impaired cardiac function. In contrast, cardiac resident macrophages were vulnerable to doxorubicin insult. The survived resident macrophages exhibited enhanced proliferation and conferred a reparative role. Global or myeloid specifically ablation of SR-A1 (class A1 scavenger receptor) inhibited proliferation of cardiac resident reparative macrophages and, therefore, exacerbated cardiomyopathy in DiCM mice. Importantly, the detrimental effect of macrophage SR-A1 deficiency was confirmed by transplantation of bone marrow. At the mechanistic level, we show that c-Myc (Avian myelocytomatosis virus oncogene cellular homolog), a key transcriptional factor for the SR-A1-P38-SIRT1 (Sirtuin 1) pathway, mediated the effect of SR-A1 in reparative macrophage proliferation in DiCM. CONCLUSIONS: The SR-A1-c-Myc axis may represent a promising target to treat DiCM through augmentation of cardiac resident reparative macrophage proliferation.

Fucoidan antagonizes diet-induced obesity and inflammation in mice.

Obesity is an escalating global pandemic posing a serious threat to human health. The intervention therapy using weight-reducing drugs, accompanied by lifestyle modification, is a strategy for the treatment of obesity. In the present study, we explored the role of fucoidan, a seaweed compound, on high-fat diet (HFD)-induced obesity in mice. We found that fucoidan treatment significantly reduced the body fat and caused redistribution of visceral and subcutaneous fat in HFD-fed mice. Meanwhile, fucoidan treatment inhibited adipocyte hypertrophy and inflammation in adipose tissue. Collectively, these results suggest that fucoidan may be a promising treatment for obesity and obesity-induced complications.

microRNA-1 Regulates NCC Migration and Differentiation by Targeting sec63.

Background/Aims: Neural crest cells play a vital role in craniofacial development, microRNA-1 (miR-1) is essential in development and disease of the cardiac and skeletal muscle, the objective of our study is to investigate effects of miR-1 on neural crest cell in the craniofacial development and its molecular mechanism. Methods: We knocked down miR-1 in zebrafish by miR-1 morpholino (MO) microinjection and observed phenotype of neural crest derivatives. We detected neural crest cell migration by time-lapse. Whole-mount in situ hybridization was used to monitor the expressions of genes involved in neural crest cell induction, specification, migration and differentiation. We performed a quantitative proteomics study (iTRAQ) and bioinformatics prediction to identify the targets of miR-1 and validate the relationship between miR-1 and its target gene sec63. Results: We found defects in the tissues derived from neural crest cells: a severely reduced lower jaw and delayed appearance of pigment cells. miR-1 MO injection also disrupted neural crest cell migration. At 24 hours post fertilization (hpf), reduced expression of tfap2a, dlx2, dlx3b, ngn1 and crestin indicated that miR-1 deficiency affected neural crest cell differentiation. iTRAQ and luciferase reporter assay identified SEC63 as a direct target gene of miR-1. The defects of miR-1 deficiency could be reversed, at least in part, by specific suppression of sec63 expression. Conclusion: miR-1 is involved in the regulation of neural crest cell development, and that it acts, at least partially, by targeting sec63 expression.

Scavenger receptor A1 attenuates aortic dissection via promoting efferocytosis in macrophages.

Macrophage class A1 scavenger receptor (SR-A1) is a pattern recognition receptor with an anti-inflammatory feature in cardiovascular diseases. However, its role in acute aortic dissection (AD) is not known yet. Using an aortic dissection model in SR-A1-deficient mice and their wild type littermates, we found that SR-A1 deficiency aggravated beta-aminopropionitrile monofumarate induced thoracic aortic dilation, false lumen formation, extracellular matrix degradation, vascular inflammation and accumulation of apoptotic cells. These pathological changes were associated with an impaired macrophage efferocytosis mediated by tyrosine-protein kinase receptor Tyro3 in vitro and in vivo. SR-A1 could directly interact with Tyro3 and was required for Tyro3 phosphorylation to activate its downstream PI3K/Akt signaling pathway. Importantly, co-culture of SR-A1-/- macrophages with apoptotic Jurkat cells resulted in less devoured apoptotic cells accompanied by swelling mitochondria and damaged ATP generation, following poor IL-10 and robust TNF-α production. Deficiency of SR-A1 did not influence phagolysosome formation during the efferocytosis. Lentiviral overexpression of Tyro3 in SR-A1-/- macrophages induced restorative phagocytosis in vitro. Administration of Tyro3 agonist protein S could restore SR-A1-/- macrophages phagocytosis in vitro and in vivo. These findings suggest that SR-A1-Tyro3 axis in macrophages mitigate AD damage by promoting efferocytosis and inhibiting inflammation.

Major vault protein suppresses lung cancer cell proliferation by inhibiting STAT3 signaling pathway.

BACKGROUND: Major vault protein (MVP) is the major component of vault, a eukaryotic organelle involved in multiple cellular processes, and is important in multiple cellular processes and diseases including the drug resistance in cancer chemotherapies. However, the role of MVP in lung cancer remains unclear. METHODS: We examined MVP expression in 120 non-small cell lung cancer (NSCLC) tumors and matched normal tissues by immunohistochemistry. Its relationship with NSCLC prognosis was determined by investigating the patient cohort and analyzing the data from a published dataset consisting with more than 1900 lung cancer patients. We further performed shRNA-introduced knockdown of MVP in Lewis lung carcinoma (LLC) cells and examined its effects on the tumor formation in a xenograft mouse model and the tumor cell proliferation, apoptosis, and signal transduction in vitro. RESULTS: We found that MVP was up-regulated significantly in tumor tissues compared with the matched tumor-adjacent normal tissues. The increased expression of MVP in lung adenocarcinoma was associated with a better prognosis. Knockdown of MVP in LLC cells promoted xenografted lung cancer formation in mice, which was accompanied with accelerated tumor cell proliferation and suppressed cell apoptosis in vitro. Knockdown of MVP stimulated STAT3 phosphorylation, nuclear localization, and activation of JAK2 and RAF/MEK/ERK pathways in LLC cells. Administration of STAT3 inhibitor WP1066 could prevent MVP knockdown induced tumorigenesis. CONCLUSIONS: Our findings demonstrate that MVP may act as a lung tumor suppressor via inhibiting STAT3 pathway. MVP would be a potential target for novel therapies of lung adenocarcinoma.

Major vault protein suppresses obesity and atherosclerosis through inhibiting IKK-NF-κB signaling mediated inflammation.

Macrophage-orchestrated, low-grade chronic inflammation plays a pivotal role in obesity and atherogenesis. However, the underlying regulatory mechanisms remain incompletely understood. Here, we identify major vault protein (MVP), the main component of unique cellular ribonucleoprotein particles, as a suppressor for NF-κB signaling in macrophages. Both global and myeloid-specific MVP gene knockout aggravates high-fat diet induced obesity, insulin resistance, hepatic steatosis and atherosclerosis in mice. The exacerbated metabolic disorders caused by MVP deficiency are accompanied with increased macrophage infiltration and heightened inflammatory responses in the microenvironments. In vitro studies reveal that MVP interacts with TRAF6 preventing its recruitment to IRAK1 and subsequent oligomerization and ubiquitination. Overexpression of MVP and its α-helical domain inhibits the activity of TRAF6 and suppresses macrophage inflammation. Our results demonstrate that macrophage MVP constitutes a key constraint of NF-κB signaling thereby suppressing metabolic diseases.

Insulin Antagonizes LPS-Induced Inflammatory Responses by Activating SR-A1/ERK Axis in Macrophages.

Insulin is a key regulator of metabolism and inflammation in the body. However, the mechanism of the anti-inflammatory effect of insulin is not fully understood. In the present study, we investigated the role of the class A1 scavenger receptor (SR-A1), a prototypic member of the pattern recognition receptor family, in the insulin-mediated suppression of inflammatory responses in macrophages. Our murine in vivo studies show that insulin can attenuate lipopolysaccharide (LPS)-induced endotoxemia in a SR-A1-dependent manner, and this was consistent with our in vitro results which demonstrate that the SR-A1 is necessary for insulin to antagonize the LPS-induced inflammatory responses in macrophages. The effect of SR-A1 on the anti-inflammatory action of insulin might be associated with the activation of the extracellular signal-regulated kinases (ERK) signaling pathway in macrophages. Insulin could inhibit macrophage polarization to a pro-inflammatory phenotype via the SR-A1/ERK cascade. Collectively, our results suggest that SR-A1 may be a pivotal element for the anti-inflammation effect of insulin in macrophages.

SR-A1 suppresses colon inflammation and tumorigenesis through negative regulation of NF-κB signaling.

Inflammatory bowel disease is characterized by chronic intestinal inflammatory disorders associated with increased risk of developing colorectal cancer. However, the detailed mechanisms are not fully understood. The aim of this study was to determine the effect of macrophage scavenger receptor class A1 (SR-A1), a pattern recognition receptor primarily expressed in macrophages, on colitis and clarify the underlying mechanisms. We found that SR-A1-/- mice had an aggravating dextran sodium sulfate-induced acute and recurring colitis. This action was associated with a robust activation of both canonical and noncanonical NF-κB signaling in the colon. Suppression of the noncanonical NF-κB signaling by SR-A1 may be via its interaction with TRAF3 in macrophages. Furthermore, the anti-inflammation effect of SR-A1 could inhibit occurrence of colitis-associated cancer in mice. These results, for the first time, demonstrate that SR-A1 as a suppressor for inflammatory bowel disease.