Cornuside alleviates psoriasis-like skin lesions in mice by relieving inflammatory effects.

Psoriasis is a chronic inflammatory skin disease substantially affecting the quality of life, with no complete cure owing to its complex pathogenesis. Cornuside, a major bioactive compound present in Cornus officinalis Sieb. et Zucc., which is a well-known traditional Chinese medicine with a variety of biological and pharmacological activities, such as anti-apoptotic, antioxidant, and anti-inflammatory properties. However, its effects on psoriasis remain unclear. Our preliminary analysis of network pharmacology showed that cornuside may be involved in psoriasis by regulating the inflammatory response and IL-17 signaling pathway. Thus, we investigated the protective role and mechanism of cornuside in the pathogenesis of psoriasis in an imiquimod (IMQ)-induced psoriasis mouse model. In-vivo experiments demonstrated that cornuside-treated mice had reduced skin erythema, scales, thickness, and inflammatory infiltration. The Psoriasis Area Severity Index score was significantly lower than that of the IMQ group. Flow cytometry analysis indicated that cornuside effectively inhibited Th1- and Th17-cell infiltration and promoted aggregation of Th2 cells in skin tissues. Cornuside also inhibited the infiltration of macrophages to the skin. Furthermore, in-vitro experiments indicated that cornuside also decreased the polarization of M1 macrophages and reduced the levels of associated cytokines. Western blotting demonstrated that cornuside suppressed the phosphorylation of c-Jun N-terminal kinase (JNK) and extracellular receptor kinase (ERK) in bone marrow-derived macrophages. Our findings indicate that cornuside has a protective effect against IMQ-induced psoriasis by inhibiting M1 macrophage polarization through the ERK and JNK signaling pathways and modulating the infiltration of immune cells as well as the expression of inflammatory factors.

Interleukin 28A aggravates Con A-induced acute liver injury by promoting the recruitment of M1 macrophages.

Immune-mediated acute hepatic injury is characterized by the destruction of a large number of hepatocytes and severe liver function damage. Interleukin-28A (IL-28A), a member of the IL-10 family, is notable for its antiviral properties. However, despite advances in our understanding of IL-28A, its role in immune-mediated acute injury remains unclear. The present study investigated the role of IL-28A in concanavalin A (Con A)-induced acute immune liver injury. After Con A injection in mice, IL-28A level significantly increased. IL-28A deficiency was found to protect mice from acute liver injury, prolong survival time, and reduce serum aspartate aminotransferase and alanine aminotransferase levels. In contrast, recombinant IL-28A aggravated liver injury in mice. The proportion of activated M1 macrophages was significantly lower in the IL-28A-deficiency group than in the wild-type mouse group. In adoptive transfer experiments, M1 macrophages from WT could exacerbate mice acute liver injury symptoms in the IL-28A deficiency group. Furthermore, the expression of proinflammatory cytokines, including tumor necrosis factor-α (TNF-α), IL-12, IL-6, and IL-1ß, by M1 macrophages decreased significantly in the IL-28A-deficiency group. Western blotting demonstrated that IL-28A deficiency could limit M1 macrophage polarization by modulating the nuclear factor (NF)-κB, mitogen-activated protein kinase (MAPK), and interferon regulatory factor (IRF) signaling pathways. In summary, IL-28A deletion plays an important protective role in the Con A-induced acute liver injury model and IL-28A deficiency inhibits the activation of M1 macrophages by inhibiting the NF-κB, MAPK, and IRF signaling pathways. These results provide a potential new target for the treatment of immune-related hepatic injury.

MicroRNA-146b protects kidney injury during urinary tract infections by modulating macrophage polarization.

Urinary tract infections (UTIs) caused by uropathogenic Escherichia coli (UPEC) can lead to severe kidney injury. However, the molecular mechanisms underlying the pathological process of kidney injury are still incompletely understood. In the present study, we demonstrate that microRNA-146b (miR-146b) deficiency aggravates kidney injury during UTIs caused by UPEC. In a mouse kidney infection model utilizing urosepsis isolate CFT073, we found that miR-146b expression significantly increased in the early stages of UPEC infection. Also, miR-146b-deficient mice displayed exacerbated inflammation in the kidney injury with severe M1 macrophage infiltration. Additionally, the results showed that miR-146b targeted interferon regulatory factor 5-regulated M1 macrophage polarization during UTIs. The results suggested that miR-146b contributed significantly to the control of kidney damage during UTIs, highlighting that miR-146b might be used as a novel therapeutic target for treating kidney injury during UTIs. IMPORTANCE Kidney injury during acute urinary tract infections (UTIs) caused by uropathogenic Escherichia coli (UPEC) is an important public health problem. However, how kidney injury develops during UPEC infection is still unclear. Although antibiotic therapy is currently an effective treatment for UTI, it cannot avoid kidney injury. MicroRNAs have gained extensive attention as essential molecules capable of regulating the autoimmune response. Among these, microRNA-146b (miR-146b) is involved in regulating inflammatory responses. In the present study, we demonstrated that miR-146b played an essential role in the development of kidney injury during UTIs caused by UPEC. The results showed that miR-146b may suppress M1 macrophage polarization and alleviate acute kidney injury. Furthermore, the miR-146b activator, agomir, in order to upregulate miR-146b, was effective in treating kidney damage by inhibiting the activation of M1 macrophages. In conclusion, our findings elucidated the mechanisms by which miR-146b alleviated kidney injury induced by UTIs, shed new light on the relationship between microRNA and bacterial infection, and provided a novel therapeutic target for treating this common bacterial infection.

Cornuside improves murine autoimmune hepatitis through inhibition of inflammatory responses.

BACKGROUND: Autoimmune hepatitis (AIH) poses an important public health concern worldwide, with few therapeutic options available. Cornuside, a primary cornel iridoid glycoside present in Cornus officinalis Sieb. et Zucc., is a well-known traditional Chinese medicine that possesses anti-inflammatory, antioxidant and anti-apoptotic properties. However, the effects of cornuside on autoimmune diseases including AIH is still not defined, neither is clear on the mechanisms of cornuside in the suppression of inflammatory responses. PURPOSE: The study was aimed to investigate the therapeutic effects of cornuside on AIH using murine models. STUDY DESIGN: A murine model of AIH induced by concanavalin A (Con A) was used to examine the pharmacological activity of cornuside in suppressing the inflammatory responses in vivo. METHODS: C57BL/6J mice were intravenously with different doses of cornuside and challenged with 18 mg/kg Con A 3 h later. Network pharmacological analysis was performed to identify the potential target genes and signaling pathways by cornuside in AIH. Next serum and liver tissues were collected 12 h after Con A injection to analyze the levels of markers for hepatic injury, apoptosis, oxidative stress, immune responses, and inflammation. RESULTS: Network pharmacological analysis revealed that cornuside may modulate oxidative stress and apoptosis in AIH. Compared with the Con A group, cornuside pretreatment significantly reduced the serum levels of alanine aminotransferase and aspartate aminotransferase, improving histopathological damage and apoptosis in the livers. In addition, cornuside decreased the levels of malondialdehyde, myeloperoxidase, but increased superoxide dismutase levels, suggesting the relieving of oxidative stress. Furthermore, cornuside suppressed the activation of T and natural killer T cells, whereas the proportion of myeloid-derived suppressor cells was significantly increased. The production of proinflammatory cytokines, including interleukin (IL)-6, IL-12, IL-1ß, and tumor necrosis factor-alpha (TNF-α), was also clearly decreased. Finally, western blot analysis displayed that cornuside inhibited the phosphorylation of extracellular receptor kinase (ERK) and c-Jun N-terminal kinase (JNK). CONCLUSIONS: We demonstrated that cornuside has protective effects for Con A-induced immune-mediated hepatitis by suppressing the oxidative stress, apoptosis, and the inflammatory responses through the ERK and JNK signaling pathways, as well as by modulating the activation and recruitment of immune cells.

Inducible nitric oxide synthase-expressing myeloid-derived suppressor cells regulated by interleukin 35 contribute to the pathogenesis of psoriasis.

Although psoriasis is classified as a T cell-mediated inflammatory disease, the contribution of myeloid cells to the pathogenesis of psoriasis is not fully understood. In the present study, we demonstrated that the expression of the anti-inflammatory cytokine interleukin-35 (IL-35) was significantly increased in patients with psoriasis with a marked increase in the number of myeloid-derived suppressor cells (MDSCs). Similar results were obtained in an imiquimod-induced psoriasis mouse model. IL-35 reduced the total number of MDSCs and their subtypes in the spleens and psoriatic skin lesions, ameliorating psoriasis. IL-35 also reduced the expression of inducible nitric oxide synthase in MDSCs, although it had no significant effect on interleukin-10 expression. Adoptive transfer of MDSCs from imiquimod-challenged mice aggravated the disease and weakened the effect of IL-35 in the recipient mice. In addition, mice transferred with MDSCs isolated from inducible nitric oxide synthase knockout mice had milder disease than those with wild-type MDSCs. Furthermore, wild-type MDSCs reversed the effects of IL-35, while MDSCs isolated from inducible nitric oxide synthase knockout mice did not affect IL-35 treatment. In summary, IL-35 may play a critical role in the regulation of iNOS-expressing MDSCs in the pathogenesis of psoriasis, highlighting IL-35 as a novel therapeutic strategy for patients with chronic psoriasis or other cutaneous inflammatory diseases.

Pyruvate Dehydrogenase Kinase 2 Accelerates Endotoxin Shock by Promoting Mitogen-Activated Protein Kinase Activation.

Endotoxin shock remains one of the major causes of mortality worldwide. Pyruvate dehydrogenase kinase (PDK) 2 is an important regulatory enzyme involved in glucose metabolism. The purpose of this study was to determine the regulatory effect of PDK2 on LPS-induced endotoxin shock and explore the mechanisms in vivo and in vitro. Here, we showed that PDK2 contributed to Toll-like receptor (TLR)-mediated inflammation. Lipopolysaccharide (LPS) activation of TLR4 pathways resulted in PDK2 upregulation in macrophages and dendritic cells (DCs). PDK2 overexpression enhanced TLR4 signaling pathway activation, whereas downregulating PDK2 expression inhibited TLR4 signaling pathway activation. Pharmacological inhibition of PDK2 significantly decreased the mortality rate and alleviated pathological injury in the lungs and livers of LPS-challenged mice, while significantly suppressing proinflammatory cytokine production. Thus, we confirmed that PDK2 is involved in LPS-induced endotoxin shock by modulating TLR4-mitogen-activated protein kinase signaling and inducing the production of proinflammatory cytokines in macrophages and DCs. Our findings highlight the importance of PDK2 as a novel target to treat septic shock.

Inducible nitric oxide synthase regulates macrophage polarization via the MAPK signals in concanavalin A-induced hepatitis.

INTRODUCTION: Acute liver inflammatory reactions contribute to many health problems; thus, it is critical to understand the underlying pathogenic mechanisms of acute hepatitis. In this study, an experimental in vivo model of concanavalin A (ConA)-induced hepatitis was used. MATERIALS AND METHODS: C57BL/6 (wild-type, WT) or inducible nitric oxide synthase-deficient (iNOS-/- ) mice were injected with PBS or 15 mg/kg ConA via tail vein. Detection of liver injury by histological examination and apoptosis, and flow cytometry to detect the effect of immune cells on liver injury. RESULTS: iNOS-/-  mice had lower levels of the liver enzymes aspartate aminotransferase and alanine aminotransferase, suggesting that they were protected against ConA-induced pathological liver injury and that iNOS participated in the regulation of hepatitis. Furthermore, iNOS deficiency was found to lower CD86 expression and suppressed the messenger RNA levels of inflammatory factors in the liver. In vitro experiments also demonstrated that iNOS deficiency suppressed the sequential phosphorylation of the mitogen-activated protein kinase pathway cascade, thereby inhibiting the M1 polarization of macrophages and consequently suppressing the transcription of inflammation factors. CONCLUSION: iNOS may contribute to ConA-induced inflammation by promoting the activation of proinflammatory macrophages.

IL-28B reprograms tumor-associated macrophages to promote anti-tumor effects in colon cancer.

The type III interferon family (IFN-III), including IFN-λ3 [interleukin (IL)-28B], has antiviral, anti-tumor, and immunomodulatory activities. Although the IL-28B anti-tumor effect has been extensively explored, its underlying mechanism remains unclear. Here, we explored IL-28B effects on colon cancer. Our results show that IL-28B significantly inhibits colon cancer progression in a mouse MC38 tumor cell colonization model and colitis-associated colorectal tumor model. Interestingly, IL-28B does not directly promote apoptosis or inhibit MC38 tumor cell proliferation in vitro. Rather, IL-28B treatment has indirect anti-tumor activity by downregulating tumor-associated macrophages. Furthermore, IL-28B inhibits M2 macrophage polarization in vitro, while also halting M2 macrophage differentiation predominantly via inhibition of the signal transducer and activator of transcription (STAT)3 and c-Jun N-terminal kinase (JNK) signaling pathways. Our findings revealed that IL-28B inhibits M2 macrophages in the tumor microenvironment to delay colon cancer progression. These findings provide novel evidence of IL-28B anti-tumor and immunomodulatory activities.

Oleandrin: A Systematic Review of its Natural Sources, Structural Properties, Detection Methods, Pharmacokinetics and Toxicology.

Oleandrin is a highly lipid-soluble cardiac glycoside isolated from the plant Nerium oleander (Apocynaceae) and is used as a traditional herbal medicine due to its excellent pharmacological properties. It is widely applied for various disease treatments, such as congestive heart failure. Recently, oleandrin has attracted widespread attention due to its extensive anti-cancer and novel anti-viral effects. However, oleandrin has a narrow therapeutic window and exhibits various toxicities, especially typical cardiotoxicity, which is often fatal. This severe toxicity and low polarity have significantly hindered its application in the clinic. This review describes natural sources, structural properties, and detection methods of oleandrin. Based on reported poisoning cases and sporadic animal experiments, the pharmacokinetic characteristics of oleandrin are summarized, so as to infer some possible phenomena, such as enterohepatic circulation. Moreover, the relevant factors affecting the pharmacokinetics of oleandrin are analyzed, and some research approaches that may ameliorate the pharmacokinetic behavior of oleandrin are proposed. With the toxicology of oleandrin being thoroughly reviewed, the development of safe clinical applications of oleandrin may be possible given potential research strategies to decrease toxicity.

SAV4 is required for ethylene-induced root hair growth through stabilizing PIN2 auxin transporter in Arabidopsis.

Root hair development is regulated by hormonal and environmental cues, such as ethylene and low phosphate. Auxin efflux carrier PIN2 (PIN-FORMED 2) plays an important role in establishing a proper auxin gradient in root tips, which is required for root hair development. Ethylene promotes root hair development through increasing PIN2 abundance in root tips, which subsequently leads to enhanced expression of auxin reporter genes. However, how PIN2 is regulated remains obscure. Here, we report that Arabidopsis thaliana sav4 (shade avoidance 4) mutant exhibits defects in ethylene-induced root hair development and in establishing a proper auxin gradient in root tips. Ethylene treatment increased SAV4 abundance in root tips. SAV4 and PIN2 co-localize to the shootward plasma membrane (PM) of root tip epidermal cells. SAV4 directly interacts with the PIN2 hydrophilic region (PIN2HL) and regulates PIN2 abundance on the PM. Vacuolar degradation of PIN2 is suppressed by ethylene, which was weakened in sav4 mutant. Furthermore, SAV4 affects the formation of PIN2 clusters and its lateral diffusion on the PM. In summary, we identified SAV4 as a novel regulator of PIN2 that enhances PIN2 membrane clustering and stability through direct protein-protein interactions. Our study revealed a new layer of regulation on PIN2 dynamics.

Pyruvate Kinase M2 Contributes to TLR-Mediated Inflammation and Autoimmunity by Promoting Pyk2 Activation.

Toll-like receptors (TLRs) play critical roles in regulating the abnormal activation of the immune cells resulting in the pathogenesis of inflammation and autoimmune diseases. Pyruvate kinase M2 (PKM2), which governs the last step of glycolysis, is involved in multiple cellular processes and pathological conditions. However, little is known about the involvement of PKM2 in regulating TLR-mediated inflammation and autoimmunity. Herein, we investigated the role of PKM2 in the activation of the TLR pathways and the pathogenesis of inflammation and autoimmune diseases. The activation of TLR4, TLR7 and TLR9 pathways was found to induce the up-regulation of PKM2 expression in macrophages, dendritic cells (DCs) and B cells. The over-expression of PKM2 promotes the activation of TLR4, TLR7 and TLR9 pathways while interference with the PKM2 expression or the addition of the PKM2 inhibitor (PKM-IN) markedly inhibited the activation of TLR4, TLR7 and TLR9 pathways. Mechanistically, PKM2 augmented the activation of TLR4, TLR7 and TLR9 pathways by promoting the activation of the proline-rich tyrosine kinase 2 (Pyk2). Intriguingly, the PKM2 inhibitor PKM2-IN significantly protected the mice from the endotoxic shock mediated by the TLR4-agonist LPS. Additionally, it alleviated the progression in the TLR7-agonist imiquimod-mediated lupus mice and spontaneous lupus MRL/lpr mice. Moreover, PKM2 expression was highly elevated in the monocytes, DCs and B cells from systemic lupus erythematous (SLE) patients compared with those from the healthy donors. Besides, the PKM2 expression level was positively correlated with the degree of activation of these immune cells. In summary, PKM2 contributed to TLR-mediated inflammation and autoimmunity and can be a valuable target to control inflammation and autoimmunity.

Corilagin Ameliorates Con A-Induced Hepatic Injury by Restricting M1 Macrophage Polarization.

Immune-mediated hepatic injury plays a key role in the initiation and pathogenesis of diverse liver diseases. However, treatment choice for immune-mediated hepatic injury remains limited. Corilagin, a natural ellagitannin extracted from various traditional Chinese medicines, has been demonstrated to exhibit multiple pharmacological activities, such as anti-inflammatory, anti-tumor, and hepatoprotective properties. The present study aimed to investigate the effects of corilagin on immune-mediated hepatic injury using a murine model of concanavalin A (Con A)-induced hepatitis, which is well-characterized to study acute immune-mediated hepatitis. Herein, mice were administered corilagin (25 mg/kg) intraperitoneally twice at 12 h intervals, and 1 h later, the mice were challenged with Con A (20 mg/kg body weight); serum and liver samples were collected after 12 h. The results showed that corilagin significantly increased the survival of mice and reduced serum alanine transaminase (ALT) and aspartate aminotransferase (AST) levels. In addition, corilagin markedly improved histopathological damage, hepatocyte apoptosis, and oxidative stress in the liver. The activation of M1 macrophages in the hepatic mononuclear cells was also significantly reduced compared with that in the control group. The expression of M1 macrophage-associated proinflammatory cytokines and genes, including interleukin (IL)-6, IL-12, and inducible nitric oxide synthase (iNOS), was also decreased after corilagin treatment. Finally, the results demonstrated that corilagin regulated macrophage polarization by modulating the mitogen-activated protein kinases (MAPK), nuclear factor (NF)-κB, and interferon regulatory factor (IRF) signaling pathways. Thus, the findings indicate that corilagin protects mice from Con A-induced immune-mediated hepatic injury by limiting M1 macrophage activation via the MAPK, NF-κB, and IRF signaling pathways, suggesting corilagin as a possible treatment choice for immune-mediated hepatic injury.

Toll-like Receptor 4 Inhibitor TAK-242 Improves Fulminant Hepatitis by Regulating Accumulation of Myeloid-Derived Suppressor Cell.

Fulminant hepatitis (FH) is an acute clinical disease with a poor prognosis and high mortality rate. The purpose of this study was to determine the protective effect of the Toll-like receptor 4 (TLR4) inhibitor TAK-242 on lipopolysaccharide (LPS)/D-galactosamine (D-GalN)-induced explosive hepatitis and explore in vivo and in vitro mechanisms. Mice were pretreated with TAK-242 for 3 h prior to LPS (10 µg/kg)/D-GalN (250 mg/kg) administration. Compared to the LPS/D-GalN group, the TAK-242 pretreatment group showed significantly prolonged survival, reduced serum alanine aminotransferase and aspartate aminotransferase levels, relieved oxidative stress, and reduced inflammatory interleukin (IL)-6, IL-12, and tumor necrosis factor-α levels. In addition, TAK-242 increased the accumulation of myeloid-derived suppressor cells (MDSCs). Next, mice were treated with an anti-Gr-1 antibody to deplete MDSCs, and adoptive transfer experiments were performed. We found that TAK-242 protected against FH by regulating MDSCs. In the in vitro studies, TAK-242 regulated the accumulation of MDSCs and promoted the release of immunosuppressive inflammatory cytokines. In addition, TAK-242 inhibited protein expression of nuclear factor-κB and mitogen-activated protein kinases. In summary, TAK-242 had a hepatoprotective effect against LPS/D-GalN-induced explosive hepatitis in mice. Its protective effect may be involved in suppressing inflammation, reducing oxidative stress, and increasing the proportion of MDSCs.

Correction: Shi, H., et al. Arctigenin Attenuates Breast Cancer Progression through Decreasing GM-CSF/TSLP/STAT3/ß-Catenin Signaling. Int. J. Mol. Sci. 2020, 21, 6357.

The authors wish to make the following correction to this paper [...].

Arctigenin Attenuates Breast Cancer Progression through Decreasing GM-CSF/TSLP/STAT3/ß-Catenin Signaling.

Invasive breast cancer is highly regulated by tumor-derived cytokines in tumor microenvironment. The development of drugs that specifically target cytokines are promising in breast cancer treatment. In this study, we reported that arctigenin, a bioactive compound from Arctium lappa L., could decrease tumor-promoting cytokines GM-CSF, MMP-3, MMP-9 and TSLP in breast cancer cells. Arctigenin not only inhibited the proliferation, but also the invasion and stemness of breast cancer cells via decreasing GM-CSF and TSLP. Mechanistically, arctigenin decreased the promoter activities of GM-CSF and TSLP via reducing the nuclear translocation of NF-κB p65 which is crucial for the transcription of GM-CSF and TSLP. Furthermore, arctigenin-induced depletion of GM-CSF and TSLP inhibited STAT3 phosphorylation and ß-catenin signaling resulting in decreased proliferation, invasion and stemness of breast cancer cells in vitro and in vivo. Our findings provide new insights into the mechanism by which tumor-promoting cytokines regulate breast cancer progression and suggest that arctigenin is a promising candidate for cytokine-targeted breast cancer therapy.

Erratum: Enrichment and characterization of cancer stem-like cells in ultra-low concentration of serum and non-adhesive culture system.

[This corrects the article on p. 1552 in vol. 10, PMID: 29887968.].

The inhibitor of autophagy SBI-0206965 aggravates atherosclerosis through decreasing myeloid-derived suppressor cells.

Atherosclerosis (AS) is currently the leading cause of mortality worldwide, with the development of new strategies to prevent the formation and rupture of atherosclerotic plaques being a paramount area of research. Amounting evidence suggests autophagy has an important role in the pathogenesis of AS and may be a potential therapeutic target. In this study, the effect of SBI-0206965(6965), a novel inhibitor of autophagy, was tested on the development of AS in apolipoprotein E deficient (ApoE-/-) mice. Systemic application of 6965 was found to aggravate AS, with increased plaque size and decreased plaque stability in comparison with the control. Of note, it was observed that 6965 decreased the proportion of myeloid-derived suppressor cells (MDSCs). Further investigation demonstrated MDSCs markedly alleviated AS in ApoE-/- mice; while 6965 reduced the viability and promoted apoptosis of MDSCs in vitro. This is the first study describing an association between autophagy and MDSCs in AS models, providing a novel mechanism to potentially target in the management of this condition.

Granulocytic myeloid-derived suppressor cells contribute to IFN-I signaling activation of B cells and disease progression through the lncRNA NEAT1-BAFF axis in systemic lupus erythematosus.

Activation of interferon (IFN)-I signaling in B cells contributes to the pathogenesis of systemic lupus erythematosus (SLE). Recent studies have shown that myeloid-derived suppressor cells (MDSCs) significantly expand in SLE patients and lupus-prone MRL/lpr mice and contribute to the pathogenesis of SLE. However, the role of SLE-derived MDSCs in regulating IFN-I signaling activation of B cells remains unknown. Here, we demonstrate that expansions of MDSCs, including granulocyte (G)-MDSCs and monocytic (M)-MDSCs, during the progression of SLE were correlated with the IFN-I signature of B cells. Interestingly, G-MDSCs from MRL/lpr mice, but not M-MDSCs, could significantly promote IFN-I signaling activation of B cells and contribute to the pathogenesis of SLE. Mechanistically, we identified that the long non-coding RNA NEAT1 was over-expressed in G-MDSCs from MRL/lpr mice and could induce the promotion of G-MDSCs on IFN-I signaling activation of B cells through B cell-activating factor (BAFF) secretion. Importantly, NEAT1 deficiency significantly attenuated the lupus symptoms in pristane-induced lupus mice. In addition, there was a positive correlation between NEAT1 and BAFF with the IFN signature in SLE patients. In conclusion, G-MDSCs may contribute to the IFN signature in SLE B cells through the NEAT1-BAFF axis, highlighting G-MDSCs as a potential therapeutic target to treat SLE.

The Caspase Inhibitor Z-VAD-FMK Alleviates Endotoxic Shock via Inducing Macrophages Necroptosis and Promoting MDSCs-Mediated Inhibition of Macrophages Activation.

Macrophages play a critical role in the pathogenesis of endotoxin shock by producing excessive amounts of pro-inflammatory cytokines. A pan-caspase inhibitor, zVAD, can be used to induce necroptosis under certain stimuli. The role of zVAD in both regulating the survival and activation of macrophages, and the pathogenesis of endotoxin shock remains not entirely clear. Here, we found that treatment of mice with zVAD could significantly reduce mortality and alleviate disease after lipopolysaccharide (LPS) challenge. Notably, in LPS-challenged mice, treatment with zVAD could also reduce the percentage of peritoneal macrophages by promoting necroptosis and inhibiting pro-inflammatory responses in macrophages. In vitro studies showed that pretreatment with zVAD promoted LPS-induced nitric oxide-mediated necroptosis of bone marrow-derived macrophages (BMDMs), leading to reduced pro-inflammatory cytokine secretion. Interestingly, zVAD treatment promoted the accumulation of myeloid-derived suppressor cells (MDSCs) in a mouse model of endotoxin shock, and this process inhibited LPS-induced pro-inflammatory responses in macrophages. Based on these findings, we conclude that treatment with zVAD alleviates LPS-induced endotoxic shock by inducing macrophage necroptosis and promoting MDSC-mediated inhibition of macrophage activation. Thus, this study provides insights into the effects of zVAD treatment in inflammatory diseases, especially endotoxic shock.

Hepatoprotective effect of capsaicin against concanavalin A-induced hepatic injury via inhibiting oxidative stress and inflammation.

Immune-mediated liver injury plays a crucial role in the pathogenesis of liver diseases, which can result from viral infections, autoimmunity, alcohol intake, and drug use. Concanavalin A (Con A)-induced hepatitis is a well-characterized murine model with similar pathophysiology to that of human viral and autoimmune hepatitis. Capsaicin, a selective agonist of the transient potential vanilloid subfamily member 1 (TRPV1) receptor, exhibits anti-inflammatory effects on various causes of inflammation. In the present study, we investigated the effect of capsaicin on Con A-induced hepatitis. Capsaicin (1 mg/kg body weight) was administered by intraperitoneal injection, after which (30 minutes), the mice were challenged intravenously with Con A (20 µg/g body weight). We collected serum for plasma transaminase analysis. Pro-inflammatory cytokine levels and hepatocyte apoptosis were assayed by ELISA and TUNEL, respectively. Liver samples were collected for real-time PCR, hematoxylin and eosin staining, and measuring oxidative stress and myeloperoxidase levels. Activation of splenocytes and hepatic mononuclear cells was analyzed by flow cytometry. Compared with control, the capsaicin-treated group showed significantly decreased aminotransferase levels and markedly prolonged mouse survival. Capsaicin pretreatment also attenuated hepatocyte apoptosis and oxidative stress. Furthermore, tumor necrosis factor-α and interferon-γ levels in serum and liver were significantly suppressed, while the percentage of myeloid-derived suppressor cells increased after capsaicin pretreatment. Our findings indicate that capsaicin pretreatment protects mice from Con A-induced hepatic damage and is partially involved in inhibiting hepatocyte apoptosis, oxidative stress, and inflammatory mediators as well as regulating activation and recruitment of intrahepatic leukocytes.