Keratinocyte and myeloid MCPIP1 have distinct roles in maintaining skin homeostasis.

The skin is a complex organ, and the intricate network between keratinocytes and immune cells is critical for ensuring skin function. Monocyte chemotactic protein-1-induced protein 1 (MCPIP1) is a ribonuclease that functions as a key negative modulator of inflammation. We previously reported that conditional deletion of MCPIP1 in keratinocytes (Mcpip1EKO) impairs skin integrity in adult mice. A similar phenotype was observed following the depletion of MCPIP1 in the myeloid compartment (Mcpip1MKO). The aim of this study was to develop a keratinocyte and myeloid double-MCPIP1 knockout mouse model to clarify the specific roles of myeloid and epidermal MCPIP1 in skin biology. Histological analyses indicated that the skin morphology changed after depletion of MCPIP1 in cells of myeloid origin as well as in keratinocytes. The thicknesses of the epidermal and subcutaneous fat layers increased in the mice with a loss of epidermal MCPIP1, whereas the loss of myeloid MCPIP1 had the opposite effect. In addition, both types of mice showed opposite responses to stimulation with 12-O-tetradecanoylphorbol-13-acetate. Transcriptomic profiling of whole-skin lysates revealed some common target transcripts in all the knockout mice. Further analyses revealed that distinct pathways are modulated following the loss of epidermal or myeloid MCPIP1. The skin morphology and inflammatory phenotype of keratinocyte and myeloid double-MCPIP1 knockout mice resembled those of mice with only keratinocyte-specific knockout of MCPIP1. Overall, myeloid and epidermal MCPIP1 play important but distinct roles in the modulation of skin-related processes.

Metformin Protects Against Acute Kidney Injury Induced by Lipopolysaccharide via Up-Regulating the MCPIP1/SIRT1 Pathway.

In the present study, we aimed to explore the effect and underlying mechanism of metformin on lipopolysaccharide (LPS)-induced acute kidney injury (AKI). A total of 24 BALB/C mice were randomly divided into four groups: control group, LPS group and metformin group (50 or 100 mg/kg). The histological changes and cell apoptosis in kidney tissues were detected by hematoxylin-eosin staining and terminal-deoxynucleotidyl transferase-mediated nick end labeling assay, respectively. Enzyme-linked immunosorbent assay was applied to determine serum levels of blood urea nitrogen (BUN), kidney injury molecule-1 (Kim-1), creatinine (Cre), tumor necrosis factor-α (TNF-α), and interleukin-1ß (IL-1ß). Western blotting analysis were carried out to confirm the expressions of monocyte chemotactic protein-inducible protein 1 (MCPIP1), silent information regulator sirtuin 1 (SIRT1), and NF-κB p65 (acetyl K310). Compared with the control group, the mice in LPS group had glomerular capillary dilatation, renal interstitial edema, tubular cell damage and apoptosis. The serum levels of BUN, KIM-1, Cre, TNF-α, and IL-1ß in LPS group were significantly higher than those in control group. Moreover, LPS also elevated the expressions of MCPIP1 and NF-κB p65 (acetyl K310) but decreased the expression of SIRT1 in kidney tissues. However, metformin distinctly decreased LPS-induced renal dysfunction, the serum levels of BUN, KIM-1, Cre, TNF-α, and IL-1ß. In addition, metformin markedly increased the expressions of MCPIP1 and SIRT1 but decreased the expression of NF-κB p65 (acetyl K310) in kidney tissues. Metformin prevented LPS-induced AKI by up-regulating the MCPIP1/SIRT1 signaling pathway and subsequently inhibiting NF-κB-mediated inflammation response.

MCPIP1 Inhibits Hepatic Stellate Cell Activation in Autocrine and Paracrine Manners, Preventing Liver Fibrosis.

BACKGROUND & AIMS: Hepatic fibrosis is characterized by enhanced deposition of extracellular matrix (ECM), which results from the wound healing response to chronic, repeated injury of any etiology. Upon injury, hepatic stellate cells (HSCs) activate and secrete ECM proteins, forming scar tissue, which leads to liver dysfunction. Monocyte-chemoattractant protein-induced protein 1 (MCPIP1) possesses anti-inflammatory activity, and its overexpression reduces liver injury in septic mice. In addition, mice with liver-specific deletion of Zc3h12a develop features of primary biliary cholangitis. In this study, we investigated the role of MCPIP1 in liver fibrosis and HSC activation. METHODS: We analyzed MCPIP1 levels in patients' fibrotic livers and hepatic cells isolated from fibrotic murine livers. In vitro experiments were conducted on primary HSCs, cholangiocytes, hepatocytes, and LX-2 cells with MCPIP1 overexpression or silencing. RESULTS: MCPIP1 levels are induced in patients' fibrotic livers compared with their nonfibrotic counterparts. Murine models of fibrosis revealed that its level is increased in HSCs and hepatocytes. Moreover, hepatocytes with Mcpip1 deletion trigger HSC activation via the release of connective tissue growth factor. Overexpression of MCPIP1 in LX-2 cells inhibits their activation through the regulation of TGFB1 expression, and this phenotype is reversed upon MCPIP1 silencing. CONCLUSIONS: We demonstrated that MCPIP1 is induced in human fibrotic livers and regulates the activation of HSCs in both autocrine and paracrine manners. Our results indicate that MCPIP1 could have a potential role in the development of liver fibrosis.

Neuroprotective Effects of Melittin Against Cerebral Ischemia and Inflammatory Injury via Upregulation of MCPIP1 to Suppress NF-κB Activation In Vivo and In Vitro.

Melittin, a principal constituent of honeybee venom, exhibits diverse biological effects, encompassing anti-inflammatory capabilities and neuroprotective actions against an array of neurological diseases. In this study, we probed the prospective protective influence of melittin on cerebral ischemia, focusing on its anti-inflammatory activity. Mechanistically, we explored whether monocyte chemotactic protein-induced protein 1 (MCPIP1, also known as ZC3H12A), a recently identified zinc-finger protein, played a role in melittin-mediated anti-inflammation and neuroprotection. Male C57/BL6 mice were subjected to distal middle cerebral artery occlusion to create a focal cerebral cortical ischemia model, with melittin administered intraperitoneally. We evaluated motor functions, brain infarct volume, cerebral blood flow, and inflammatory marker levels within brain tissue, employing quantitative real-time polymerase chain reaction, enzyme-linked immunosorbent assays, and western blotting. In vitro, an immortalized BV-2 microglia culture was stimulated with lipopolysaccharide (LPS) to establish an inflammatory cell model. Post-melittin exposure, cell viability, and cytokine expression were examined. MCPIP1 was silenced using siRNA in LPS-induced BV-2 cells, with the ensuing nuclear translocation of nuclear factor-κB assessed through cellular immunofluorescence. In vivo, melittin enhanced motor functions, diminished infarction, fostered blood flow restoration in ischemic brain regions, and markedly inhibited the expression of inflammatory cytokines (interleukin-1ß, interleukin-6, tumor necrosis factor-α, and nuclear factor-κB). In vitro, melittin augmented MCPIP1 expression in LPS-induced BV-2 cells and ameliorated inflammation-induced cell death. The neuroprotective effect conferred by melittin was attenuated upon MCPIP1 knockdown. Our findings establish that melittin-induced tolerance to ischemic injury is intrinsically linked with its anti-inflammatory capacity. Moreover, MCPIP1 is, at the very least, partially implicated in this process.

Investigation of the shared gene signatures and molecular mechanisms between obstructive sleep apnea syndrome and asthma.

BACKGROUND: Obstructive sleep apnea syndrome (OSAS) is highly related with asthma from the epidemiology to pathogenesis, while the underlying mechanism is still unclear. Herein, we aimed to reveal the shared gene signatures and molecular mechanisms underlying the coexistence of OSAS and asthma and verified relating pathway in mouse models. We downloaded GSE75097 of OSAS and GSE165934 of asthma from GEO database and performed differential expression analysis and functional enrichment analysis to screen differentially expressed genes (DEGs) and potential pathogenic pathway. PPI network was constructed with the STRING database. Hub genes were identified with cytoHubba and immune infiltration analysis was performed with cibersort for further verification. Potential drugs were screened with Comparative Toxicogenomics Database and miRNA-gene network was constructed. Besides, to test the pulmonary function and inflammatory cytokine, mouse models with OSAS and asthma were constructed, followed by validating the involvement of NOD1/NOD2-RIPK2-NF-κB-MCPIP-1 pathway in associated diseases. RESULTS: In total, 104 DEGs were identified, in which PLAUR, RIPK2, PELI1, ZC3H12A, and TNFAIP8 are the hub genes, while NOD-like receptor signaling pathway and apoptosis signaling pathway were the potential influential pathways. Increased γδT cells and neutrophils were detected in asthma patients through immune infiltration analysis. Significant difference was detected among genders in OSAS, and acetaminophen is a potential drug in the comorbidity by screening the drugs in the Comparative Toxicogenomics Database. Mice with OSAS and asthma presented with worse pulmonary function and higher levels of inflammatory cytokines. The relative proteins, including NOD1, NOD2, RIPK2, NF-κB, and MCPIP-1, were up-regulated in mice with the OSAS and asthma. CONCLUSIONS: This research firstly elucidates NOD1/NOD2-RIPK2-NF-κB-MCPIP-1 pathway as the shared pathway in the development of OSAS and asthma through bioinformatics and experimental methods. There is an interactive deterioration model between OSAS and asthma. This study may provide some potential biomarkers in the future research of the underlying pathogenesis and treatment of comorbidity of OSAS and asthma.

Let-7g Upregulation Attenuated the KRAS-PI3K-Rac1-Akt Axis-Mediated Bioenergetic Functions.

The aberrant activation of signaling pathways contributes to cancer cells with metabolic reprogramming. Thus, targeting signaling modulators is considered a potential therapeutic strategy for cancer. Subcellular fractionation, coimmunoprecipitation, biochemical analysis, and gene manipulation experiments revealed that decreasing the interaction of kirsten rat sarcoma viral oncogene homolog (KRAS) with p110α in lipid rafts with the use of naringenin (NGN), a citrus flavonoid, causes lipid raft-associated phosphatidylinositol 3-kinase (PI3K)-GTP-ras-related C3 botulinum toxin substrate 1 (Rac1)-protein kinase B (Akt)-regulated metabolic dysfunction of glycolysis and mitochondrial oxidative phosphorylation (OXPHOS), leading to apoptosis in human nasopharyngeal carcinoma (NPC) cells. The use of lethal-7g (let-7g) mimic and let-7g inhibitor confirmed that elevated let-7g resulted in a decrease in KRAS expression, which attenuated the PI3K-Rac1-Akt-BCL-2/BCL-xL-modulated mitochondrial energy metabolic functions. Increased let-7g depends on the suppression of the RNA-specificity of monocyte chemoattractant protein-induced protein-1 (MCPIP1) ribonuclease since NGN specifically blocks the degradation of pre-let-7g by NPC cell-derived immunoprecipitated MCPIP1. Converging lines of evidence indicate that the inhibition of MCPIP1 by NGN leads to let-7g upregulation, suppressing oncogenic KRAS-modulated PI3K-Rac1-Akt signaling and thereby impeding the metabolic activities of aerobic glycolysis and mitochondrial OXPHOS.

MCPIP-1 knockdown enhances endothelial colony-forming cell angiogenesis via the TFRC/AKT/mTOR signaling pathway in the ischemic penumbra of MCAO mice.

Cerebral ischemia is a serious disease characterized by brain tissue ischemia and hypoxic necrosis caused by the blockage of blood vessels within the central nervous system. Although stem cell therapy is a promising approach for treating ischemic stroke, the inflammatory, oxidative, and hypoxic environment generated by cerebral ischemia greatly reduces the survival and therapeutic effects of transplanted stem cells. Endothelial colony-forming cells (ECFCs) are a class of precursor cells with strong proliferative potential that can migrate and differentiate directly into mature vascular endothelial cells. Consequently, ECFCs can exert significant therapeutic and reparative effects in diseases associated with vascular injury. Monocyte chemoattractant protein-induced protein 1 (MCPIP-1) exerts multiple biological effects; however, no studies have yet reported its role in the angiogenic function of ECFCs. In this study, we performed Proteome Profiler™ Human Angiogenesis Antibody arrays and tandem mass tag protein profiling to investigate the effect of MCPIP-1 on ECFCs. We demonstrated that MCPIP-1 knockdown enhanced the proliferation, migration, and in vivo and in vitro angiogenic capacity of ECFCs by upregulating the transferrin receptor-activated AKT/m-TOR signaling pathway to promote cellular trophic factor secretion. Furthermore, we found that the lateral ventricular transplantation of ECFCs with lentiviral MCPIP-1 knockdown into mice with middle cerebral artery occlusion increased serum vacular endothelial growth factor(VEGF), angiopoietin-1, and HIF-1a levels, enhanced neovascularization and neurogenesis in the ischemic penumbra, reduced the size of cerebral infarcts, and promoted neurological recovery. Together, these findings suggest new avenues for enhancing the therapeutic efficacy of ECFCs.

Huoluo Xiaoling Pellet promotes microglia M2 polarization through increasing MCPIP1 expression for ischemia stroke alleviation.

Huoluo Xiaoling Pellet (HXP), a Chinese patent medicine, is commonly administered for the treatment of treat ischemic strokes. MCPIP1, an inducible suppressor of the inflammatory response, is a regulator of microglial M2 polarization. This study aimed to explore whether HXP can promote microglial M2 polarization by upregulating MCPIP1 expression, consequently mitigating cerebral ischemic injury. Our study involved 85 Sprague-Dawley rats (weighing 250-280 g). We established middle cerebral artery occlusion (MCAO) and oxygen-glucose deprivation-reoxygenation (OGD/R) models with MCPIP1 knockdown to assess the effects of HXP on ischemic strokes. Our findings show that HXP reduced brain water content, improved neurological function, and inhibited the expression of inflammatory factors in the brain tissues of MCAO rats. The neuroprotective effects of HXP on cerebral ischemic injuries were compromised by MCPIP1 knockdown. Immunofluorescence results indicated that the expression of microglia marker Iba1 and M2 phenotypic marker CD206 was upregulated in MCAO rats and OGD/R-treated microglia. Administration of HXP significantly reduced Iba1 expression and facilitated CD206 expression, an effect that was counteracted by sh-MCPIP1 transfection. Western blotting revealed that HXP treatment augmented the expression of MCPIP1, microglial M2 marker proteins (CD206 and Arg1), and PPARγ, while reducing the expression of microglial M1 marker proteins (CD16 and iNOS) in MCAO rats and OGD/R-induced microglia. MCPIP1 knockdown suppressed HXP-mediated upregulation of MCPIP1, CD206, Arg1, and PPARγ, as well as the downregulation of CD16 and iNOS. Our findings suggest that HXP primarily ameliorates ischemic stroke through the upregulation of MCPIP1, which in turn induces microglial M2 polarization.

Depletion of Mcpip1 in murine myeloid cells results in intestinal dysbiosis followed by allergic inflammation.

MCPIP1 (called also Regnase-1) is a negative regulator of inflammation. Knockout of the Zc3h12a gene, encoding Mcpip1 in cells of myeloid origin (Mcpip1MKO), has a pathological effect on many organs. The aim of this study was to comprehensively analyze pathological changes in the skin caused by Mcpip1 deficiency in phagocytes with an emphasis on its molecular mechanism associated with microbiome dysbiosis. Mcpip1MKO mice exhibited spontaneous wound formation on the skin. On a molecular level, the Th2-type immune response was predominantly characterized by an increase in Il5 and Il13 transcript levels, as well as eosinophil and mast cell infiltration. Irritation by DNFB led to a more severe skin contact allergy in Mcpip1MKO mice. Allergic reactions on the skin were strongly influenced by gut dysbiosis and enhanced systemic dissemination of bacteria. This process was followed by activation of the C/EBP pathway in peripheral macrophages, leading to local changes in the cytokine microenvironment that promoted the Th2 response. A reduced bacterial load inhibited allergic inflammation, indicating the role of intestinal dysbiosis in the development of skin diseases. Our results clearly show that MCPIP1 in phagocytes is an essential negative regulator that controls the gut-skin axis.

Localization and expression profiles of gingival monocyte chemoattractant protein-1-induced protein-1 (MCPIP-1) and mucosa-associated lymphoid tissue lymphoma translocation protein 1 (MALT-1).

OBJECTIVES: The purposes of this study were to localize monocyte chemoattractant protein-1-induced protein-1 (MCPIP-1) and its suppressor mucosa-associated lymphoid tissue lymphoma translocation protein 1 (MALT-1) in gingival tissues and to profile their protein expression levels in relation to the clinical inflammation, Porphyromonas gingivalis colonization, and interleukin (IL)-8 levels. MATERIALS AND METHODS: Study samples were collected from two independent study populations: (1) Gingival tissues were collected from eight periodontally healthy individuals and eight periodontitis patients to localize MCPIP-1 and MALT-1 immunohistochemically, and (2) forty-one gingival tissue samples with marginal, mild, or moderate to severe inflammation were collected from 20 periodontitis patients to determine MCPIP-1 and MALT-1 levels using immunoblots, P. gingivalis levels with qPCR, P. gingivalis gingipain activities with fluorogenic substrates, and IL-8 levels with multiplex technique. RESULTS: MCPIP-1 was detectable in the epithelium and in connective tissue, being especially prominent around the blood vessel walls in healthy periodontal tissues. MALT-1 was observed at all layers of gingival epithelium and especially around the accumulated inflammatory cells in connective tissue. No difference in gingival tissue MCPIP-1 and MALT-1 levels was observed in relation to the severity of gingival inflammation. MALT-1 levels were elevated (p = 0.023) with the increase in tissue P. gingivalis levels, and there was an association between MALT-1 and IL-8 levels (ß = 0.054, p = 0.001). CONCLUSIONS: Interactions of MALT-1 levels with gingival tissue P. gingivalis counts and IL-8 levels suggest that activation of MALT-1 can take part in P. gingivalis-regulated host immune responses. CLINICAL RELEVANCE: Pharmacological targeting the crosstalk between immune response and MCPIP-1/MALT-1 may have benefits in periodontal treatment.

MCPIP1 alleviates inflammatory response through inducing autophagy in Aspergillus fumigatus keratitis.

Fungal keratitis (FK) is a serious corneal infection caused by pathogenic fungi. Monocyte chemoattractant protein-induced protein 1 (MCPIP1) plays an important role in restricting the inflammatory response in various immune disorders. However, the function of MCPIP1 in Aspergillus fumigatus (A. fumigatus) keratitis is unclear. In the present study, we found that A. fumigatus infection promotes the expression of MCPIP1 in human corneal epithelial cells (HCECs) and in mouse corneas. Overexpression of MCPIP1 decreased the production of inflammatory cytokines, including TNF-α, IL-6, and IL-1ß, while knockdown of MCPIP1 increased the expression of these cytokines. MCPIP1 enhanced autophagy flux by inhibiting the mTOR signaling in HCECs with A. fumigatus infection. Further study showed that inhibition of autophagy using chloroquine reverses the anti-inflammatory effect of MCPIP1 in HCECs infected with A. fumigatus. Moreover, MCPIP1 alleviated the severity of keratitis and inhibited the expression of inflammatory cytokines by activating autophagy in an FK mouse model. In conclusion, our study demonstrated that MCPIP1 alleviates the severity of A. fumigatus keratitis by inducing mTOR-mediated autophagy in HCECs and in a mouse model. Exogenous use of MCPIP1 protein may have potential applications in FK clinical therapy.

MCPIP-1-Mediated Immunosuppression of Neutrophils Exacerbates Acute Bacterial Peritonitis and Liver Injury.

Monocyte chemotactic protein-1-induced protein-1 (MCPIP-1) is highly expressed in activated immune cells and negatively regulates immune responses, while the mechanisms underlying the immunoregulation of neutrophils in acute bacterial infection and liver injury remain elusive. Here, we examined the role of MCPIP-1 in regulating neutrophil functions during acute bacterial peritonitis and liver injury. Mice with myeloid cell-specific overexpression (McpipMye-tg) or knockout (McpipΔMye) of MCPIP-1 were generated. We found that reactive oxygen species and myeloperoxidase production, formation of neutrophil extracellular traps, and migratory capacity were deficient in McpipMye-tg neutrophils but enhanced in McpipΔMye neutrophils. The recruitment of neutrophils and pathogen clearance were markedly suppressed in McpipMye-tg mice following intraperitoneal infection with Salmonella typhimurium while intensified in McpipΔMye mice. Severe acute S. typhimurium-infected peritonitis and liver injury occurred in McpipMye-tg mice but were alleviated in McpipΔMye mice. RNA sequencing, RNA-binding protein immunoprecipitation and qPCR analysis revealed that MCPIP-1 downregulated the protective functions of neutrophils via degrading the mRNA of cold inducible RNA-binding protein. Consistently, MCPIP-1 was highly expressed in neutrophils of patients with acute infectious diseases, especially in those with liver injury. Collectively, we uncover that MCPIP-1 negatively regulates the antibacterial capacities of neutrophils, leading to exacerbating severe acute bacterial peritonitis and liver injury. It may serve as a candidate target for maintaining neutrophil homeostasis to control acute infectious diseases.

MCPIP1 alleviated alcohol-induced immune dysfunction via the MAPK/ERK signaling pathway.

RATIONALE: In recent years, monocyte chemotactic protein-induced protein 1 (MCPIP1) has been reported to control inflammation via IL-10. OBJECTIVES: The aims of this study were to determine (1) whether MCPIP1 can repair damage to the immune system after alcohol use and (2) whether MCPIP1 can repair the immune function impaired by alcohol use through the MAPK/ERK signaling pathway. Our results will inform the treatment of immune dysfunction caused by alcohol consumption. METHODS: Scrambled shRNA or MCPIP-1-shRNA carried by the lentiviral vector (50µl each at 1×108TU/ml) was injected retrogradely through the pancreatic duct to pretreat male C57BL/6 mice. Five days after the injection, mice were exposed to intragastric ethanol infusion (5g/kg, 25% ethanol w/v) daily or vehicle for 10 days. RESULTS: MCPIP-1 protein was increased in the pancreas after alcohol exposure. MCPIP-1 shRNA specifically decreased MCPIP-1 protein expression and mRNA level in the pancreas. Specific knockdown of MCPIP-1 exacerbates pancreatic necrosis, interstitial edema, and inflammatory infiltrates after alcohol exposure. Meanwhile, specific knockdown of MCPIP-1 also increased pancreatic pro-inflammatory cytokine (IL-6 and IL-1ß), chemokine MCP-1, and chemokine receptor 2 (CCR2) after alcohol exposure. What's more, p-JNK and p-ERK in the pancreas were all similarly increased in response to pancreas-specific knockdown of MCPIP-1 during alcohol exposure. CONCLUSIONS: Taken together, the results above suggested that MCPIP1 repairs the immune function impaired by alcohol use via stimulating JNK and ERK pathways. Our results will inform the treatment of immune dysfunction caused by alcohol consumption.

MCPIP1 promotes cell proliferation, migration and angiogenesis of glioma via VEGFA-mediated ERK pathway.

Glioma is the most common primary malignant intracranial tumor in the population, and is often associated with abundant angiogenesis. However, how angiogenesis is regulated during glioma progression is still poorly understood. Data mining of cancer patient database shows that MCPIP1 is positively correlated with VEGFA expression and negatively with survival. In this study, we report that overexpressed MCPIP1 in glioma cells is a boost of angiogenesis. Mechanistically, MCPIP1 upregulates the expression of VEGFA in glioma, and promote the secretion of VEGFA to the surroundings, which could stimulate angiogenesis through ERK pathway. Blocking VEGFA expression and secretion inhibited MCPIP1-mediated angiogenesis and glioma progression in vitro and xenograft models. Collectively, these results identify a critical role for MCPIP1 in angiogenesis and glioma progression by regulating the VEGFA-mediated ERK pathway, suggesting that targeting MCPIP1 may be a potential glioma-selective therapeutic strategy.

Porcine Reproductive and Respiratory Syndrome Virus Adapts Antiviral Innate Immunity via Manipulating MALT1.

To fulfill virus replication and persistent infection in hosts, viruses have to find ways to compromise innate immunity, including timely impedance on antiviral RNases and inflammatory responses. Porcine reproductive and respiratory syndrome virus (PRRSV) is a major swine pathogen causing immune suppression. MALT1 is a central immune regulator in both innate and adaptive immunity. In this study, MALT1 was confirmed to be induced rapidly upon PRRSV infection and mediate the degradation of two anti-PRRSV RNases, MCPIP1 and N4BP1, relying on its proteolytic activity, consequently facilitating PRRSV replication. Multiple PRRSV nsps, including nsp11, nsp7ß, and nsp4, contributed to MALT1 elicitation. Interestingly, the elevated expression of MALT1 began to decrease once intracellular viral expression reached a high enough level. Higher infection dose brought earlier MALT1 inflection. Further, PRRSV nsp6 mediated significant MALT1 degradation via ubiquitination-proteasome pathway. Downregulation of MALT1 suppressed NF-κB signals, leading to the decrease in proinflammatory cytokine expression. In conclusion, MALT1 expression was manipulated by PRRSV in an elaborate manner to antagonize precisely the antiviral effects of host RNases without excessive and continuous activation of inflammatory responses. These findings throw light on the machinery of PRRSV to build homeostasis in infected immune system for viral settlement. IMPORTANCE PRRSV is a major swine pathogen, suppresses innate immunity, and causes persistent infection and coinfection with other pathogens. As a central immune mediator, MALT1 plays essential roles in regulating immunity and inflammation. Here, PRRSV was confirmed to manipulate MALT1 expression in an accurate way to moderate the antiviral immunity. Briefly, multiple PRRSV nsps induced MALT1 protease to antagonize anti-PRRSV RNases N4BP1 and MCPIP1 upon infection, thereby facilitating viral replication. In contrast, PRRSV nsp6 downregulated MALT1 expression via ubiquitination-proteasome pathway to suppress the inflammatory responses upon infection aggravation, contributing to immune defense alleviation and virus survival. These findings revealed the precise expression control on MALT1 by PRRSV for antagonizing antiviral RNases, along with recovering immune homeostasis. For the first time, this study enlightens a new mechanism of PRRSV adapting antiviral innate immunity by modulating MALT1 expression.

MCPIP1 regulates focal adhesion kinase and Rho GTPase-dependent migration in clear cell renal cell carcinoma.

Metastasis is responsible for as many as 90% of cancer-associated deaths in patients. The metastatic process is a result of tumor cell migration and invasion associated with morphological changes and increased expression of several genes involved in cell migration. We have already shown that monocyte chemotactic protein-1-induced protein-1 (MCPIP1), a negative regulator of inflammatory processes, influences cell morphology, prevents the epithelial to mesenchymal transition program, and regulates metastasis in clear cell renal cell carcinoma (ccRCC). However, the mechanism by which MCPIP1 influences cell migratory potential is unknown. In this study, we investigated how MCPIP1 affects ccRCC cell migration. We showed that MCPIP1 prevents morphological transformation and drastically reduces the migration of ccRCC cells. MCPIP1 decreases the levels of Rho GTPases and reduces the phosphorylation of FAK at Tyr-397 and Tyr-861 and Src at Tyr-418. The loss of MCPIP1 RNase activity results in actin remodeling, an increase in the levels of Rho proteins and the phosphorylation of FAK on Tyr-397, which leads to Tyr-418 Src phosphorylation and an increase in migration activity. Moreover, we observed increased expression of IL-1ß in ccRCC cells and tumors lacking MCPIP1 RNase activity. Additionally, microarray analysis of tissues from patients with ccRCC revealed changes in the expression of several genes correlated with migration as tumor progression occurred. This study indicates an important role of MCPIP1 as a regulator of migratory potential in ccRCC.

Macrophage-Specific MCPIP1/Regnase-1 Attenuates Kidney Ischemia-Reperfusion Injury by Shaping the Local Inflammatory Response and Tissue Regeneration.

Sterile inflammation either resolves the initial insult or leads to tissue damage. Kidney ischemia/reperfusion injury (IRI) is associated with neutrophilic infiltration, enhanced production of inflammatory mediators, accumulation of necrotic cells and tissue remodeling. Macrophage-dependent microenvironmental changes orchestrate many features of the immune response and tissue regeneration. The activation status of macrophages is influenced by extracellular signals, the duration and intensity of the stimulation, as well as various regulatory molecules. The role of macrophage-derived monocyte chemoattractant protein-induced protein 1 (MCPIP1), also known as Regnase-1, in kidney ischemia-reperfusion injury (IRI) and recovery from sterile inflammation remains unresolved. In this study, we showed that macrophage-specific Mcpip1 deletion significantly affects the kidney phenotype. Macrophage-specific Mcpip1 transgenic mice displayed enhanced inflammation and loss of the tubular compartment upon IRI. We showed that MCPIP1 modulates sterile inflammation by negative regulation of Irf4 expression and accumulation of IRF4+ cells in the tissue and, consequently, suppresses the post-ischemic kidney immune response. Thus, we identified MCPIP1 as an important molecular sentinel of immune homeostasis in experimental acute kidney injury (AKI) and renal fibrosis.

Loss of epidermal MCPIP1 is associated with aggressive squamous cell carcinoma.

BACKGROUND: Squamous cell carcinoma (SCC) of the skin is a common form of nonmelanoma skin cancer. Monocyte chemotactic protein 1-induced protein 1 (MCPIP1), also called Regnase-1, is an RNase with anti-inflammatory properties. In normal human skin, its expression is predominantly restricted to the suprabasal epidermis. The main aim of this study was to investigate whether MCPIP1 is involved in the pathogenesis of SCC. METHODS: We analyzed the distribution of MCPIP1 in skin biopsies of patients with actinic keratoses (AKs) and SCCs. To explore the mechanisms by which MCPIP1 may modulate tumorigenesis in vivo, we established a mouse model of chemically induced carcinogenesis. RESULTS: Skin expression of MCPIP1 changed during the transformation of precancerous lesions into cutaneous SCC. MCPIP1 immunoreactivity was high in the thickened area of the AK epidermis but was predominantly restricted to keratin pearls in fully developed SCC lesions. Accelerated development of chemically induced skin tumors was observed in mice with loss of epidermal MCPIP1 (Mcpip1eKO). Papillomas that developed in Mcpip1eKO mouse skin were larger and characterized by elevated expression of markers typical of keratinocyte proliferation and tumor angiogenesis. This phenotype was correlated with enhanced expression of IL-6, IL-33 and transforming growth factor-beta (TGF-ß). Moreover, our results demonstrated that in keratinocytes, the RNase MCPIP1 is essential for the negative regulation of genes encoding SCC antigens and matrix metallopeptidase 9. CONCLUSIONS: Overall, our results provide a mechanistic understanding of how MCPIP1 contributes to the development of epidermoid carcinoma.

Monocyte Chemotactic Protein-Induced Protein 1 (MCPIP-1): A Key Player of Host Defense and Immune Regulation.

Inflammatory response is a host-protective mechanism against tissue injury or infections, but also has the potential to cause extensive immunopathology and tissue damage, as seen in many diseases, such as cardiovascular diseases, neurodegenerative diseases, metabolic syndrome and many other infectious diseases with public health concerns, such as Coronavirus Disease 2019 (COVID-19), if failure to resolve in a timely manner. Recent studies have uncovered a superfamily of endogenous chemical molecules that tend to resolve inflammatory responses and re-establish homeostasis without causing excessive damage to healthy cells and tissues. Among these, the monocyte chemoattractant protein-induced protein (MCPIP) family consisting of four members (MCPIP-1, -2, -3, and -4) has emerged as a group of evolutionarily conserved molecules participating in the resolution of inflammation. The focus of this review highlights the biological functions of MCPIP-1 (also known as Regnase-1), the best-studied member of this family, in the resolution of inflammatory response. As outlined in this review, MCPIP-1 acts on specific signaling pathways, in particular NFκB, to blunt production of inflammatory mediators, while also acts as an endonuclease controlling the stability of mRNA and microRNA (miRNA), leading to the resolution of inflammation, clearance of virus and dead cells, and promotion of tissue regeneration via its pleiotropic effects. Evidence from transgenic and knock-out mouse models revealed an involvement of MCPIP-1 expression in immune functions and in the physiology of the cardiovascular system, indicating that MCPIP-1 is a key endogenous molecule that governs normal resolution of acute inflammation and infection. In this review, we also discuss the current evidence underlying the roles of other members of the MCPIP family in the regulation of inflammatory processes. Further understanding of the proteins from this family will provide new insights into the identification of novel targets for both host effectors and microbial factors and will lead to new therapeutic treatments for infections and other inflammatory diseases.