Interferon γ Regulates Acute and Latent Murine Cytomegalovirus Infection and Chronic Disease of the Great Vessels

To define immune mechanisms that regulate chronic and latent herpesvirus infection, we analyzed the role of interferon γ (IFN-γ) during murine cytomegalovirus (MCMV) infection. Lethality studies demonstrated a net protective role for IFN-γ, independent of IFN-α/β, during acute MCMV infection. Mice lacking the IFN-γ receptor (IFN-γR^−/−) developed and maintained striking chronic aortic inflammation. Arteritis was associated with inclusion bodies and MCMV antigen in the aortic media. To understand how lack of IFN-γ responses could lead to chronic vascular disease, we evaluated the role of IFN-γ in MCMV latency. MCMV-infected IFN-γR^−/− mice shed preformed infectious MCMV in spleen, peritoneal exudate cells, and salivary gland for up to 6 mo after infection, whereas the majority of congenic control animals cleared chronic productive infection. However, the IFN-γR was not required for establishment of latency. Using an in vitro explant reactivation model, we showed that IFN-γ reversibly inhibited MCMV reactivation from latency. This was at least partly explained by IFN-γ– mediated blockade of growth of low levels of MCMV in tissue explants. These in vivo and in vitro data suggest that IFN-γ regulation of reactivation from latency contributes to control of chronic vascular disease caused by MCMV. These studies are the first to demonstrate that a component of the immune system (IFN-γ) is necessary to regulate MCMV-associated elastic arteritis and latency in vivo and reactivation of a herpesvirus from latency in vitro. This provides a new model for analysis of the interrelationships among herpesvirus latency, the immune system, and chronic disease of the great vessels.     

Loganin attenuates interleukin-1β-induced chondrocyte inflammation,cartilage degeneration,and rat synovial inflammation by regulating TLR4/MyD88/NF-κB

ObjectiveInflammation plays a crucial part in osteoarthritis (OA) development. This work aimed to explore loganin’s role and molecular mechanism in inflammation and clarify its anti-inflammatory effects in OA treatment.MethodsChondrocytes were stimulated using interleukin (IL)-1β and loganin at two concentrations (1 μM and 10 μM). Nitric oxide (NO) and prostaglandin E2 (PGE2) expression was assessed. Real-time polymerase chain reaction was used to evaluate inducible NO synthase (iNOS), cyclooxygenase (COX)-2, IL-6, and tumor necrosis factor (TNF)-α mRNA levels. Western blot was used to investigate TLR4, MyD88, p-p65, and IκB-α expression. p65 nuclear translocation, synovial inflammatory response, and cartilage degeneration were also assessed.ResultsLoganin significantly reduced IL-1β-mediated PGE2, NO, iNOS, and COX-2 expression compared with that of the IL-1β stimulation group. The TLR4/MyD88/NF-κB pathway was suppressed by loganin, which decreased inflammatory cytokine (TNF-α and IL-6) levels compared with those of the IL-1β stimulation group. Loganin inhibited IL-1β-mediated NF-κB p65 nuclear translocation compared with that of the IL-1β stimulation group. Loganin partially suppressed cartilage degeneration and the synovial inflammatory response in vivo.ConclusionThis work demonstrated that loganin inhibited IL-1β-mediated inflammation in rat chondrocytes through TLR4/MyD88/NF-κB pathway regulation, thereby reducing rat cartilage degeneration and the synovial inflammatory response.     

Topical hypochlorite ameliorates NF-κB–mediated skin diseases in mice

Nuclear factor-κB (NF-κB) regulates cellular responses to inflammation and aging, and alterations in NF-κB signaling underlie the pathogenesis of multiple human diseases. Effective clinical therapeutics targeting this pathway remain unavailable. In primary human keratinocytes, we found that hypochlorite (HOCl) reversibly inhibited the expression of CCL2 and SOD2, two NF-κB–dependent genes. In cultured cells, HOCl inhibited the activity of inhibitor of NF-κB kinase (IKK), a key regulator of NF-κB activation, by oxidizing cysteine residues Cys114 and Cys115. In NF-κB reporter mice, topical HOCl reduced LPS-induced NF-κB signaling in skin. We further evaluated topical HOCl use in two mouse models of NF-κB–driven epidermal disease. For mice with acute radiation dermatitis, topical HOCl inhibited the expression of NF-κB–dependent genes, decreased disease severity, and prevented skin ulceration. In aged mice, topical HOCl attenuated age-dependent production of p16^INK4a and expression of the DNA repair gene Rad50. Additionally, skin of aged HOCl-treated mice acquired enhanced epidermal thickness and proliferation, comparable to skin in juvenile animals. These data suggest that topical HOCl reduces NF-κB–mediated epidermal pathology in radiation dermatitis and skin aging through IKK modulation and motivate the exploration of HOCl use for clinical aims.     

Epidermal IL-15Rα acts as an endogenous antagonist of psoriasiform inflammation in mouse and man

Stromal cells at epithelial surfaces contribute to innate immunity by sensing environmental danger signals and producing proinflammatory cytokines. However, the role of stromal cells in controlling local inflammation is unknown. We show that endogenous soluble IL-15 receptor α (IL-15Rα) derived from epidermal stroma, notably keratinocytes, protects against dendritic cell/IL-15-mediated, T cell-driven skin inflammation in vivo, and is relevant to human psoriasis. Selective lack of IL-15Rα on stromal epidermal cells exacerbated psoriasiform inflammation in animals. Epidermal IL-15Rα was shed by keratinocytes via proteolytic cleavage by matrix metalloproteinases upon stimulation with proinflammatory cytokines to counteract IL-15–induced proliferation of IL-17⁺ αβ and γδ T cells and production of TNF, IL-23, IL-17, and IL-22 during skin inflammation. Notably, administration of soluble IL-15Rα was able to repress secretion of IL-1β, IL-6, and TNF by keratinocytes, dampen expansion of IL-17⁺ αβ and γδ T cells in vivo, and prevent psoriasis in two mouse models, including human xenograft AGR mice. Serum levels of soluble IL-15Rα negatively correlated with disease severity, and levels rose upon successful treatment of psoriasis in patients. Thus, stressed epidermal stromal cells use soluble IL-15Rα to dampen chronic inflammatory skin disease.Psoriasis is a chronic, relapsing-remitting inflammatory disorder mediated by effector T cells, including CD4⁺ and CD8⁺ αβ and γδ T cells (Lowes et al., 2007; Nestle et al., 2009). These T cells secrete an array of proinflammatory cytokines, including tumor necrosis factor-α (TNF), interferon-γ (IFN-γ), IL-17, and IL-22, to stimulate proliferation of keratinocytes and recruit inflammatory cells (Di Meglio et al., 2011; Lowes et al., 2007). Notably, αβ T cells appear to be crucial in the chronic-relapsing phase of the disease, where these cells become resident in the skin, presumably as memory T cells dependent on IL-15 and other homeostatic cytokines (Boyman et al., 2007). Upon induction of a psoriatic lesion, CD8⁺ T cells, notably α₁β₁ integrin⁺ cells, home to the epidermis and correlate with epidermal thickening (acanthosis) and elongation of dermal papillae (papillomatosis), leading to enhanced interdigitation of epidermis and dermis (Boyman et al., 2004; Conrad et al., 2007). As for γδ T cells, the involvement of these cells has recently been implicated in the pathogenesis of psoriasis (Laggner et al., 2011), especially during the early stages of psoriasiform skin inflammation in mouse models (Cai et al., 2011; Pantelyushin et al., 2012).Furthermore, DCs appear to be involved very early in the pathogenesis of psoriasis by producing type I IFNs (Nestle et al., 2005). Interestingly, treatment with imiquimod (IMQ), an agonist of Toll-like receptors (TLR) 7 and 8, can stimulate DCs to produce type I IFNs, and thus exacerbate psoriasis in patients (Gilliet et al., 2004). Moreover, treatment of normal mice with IMQ results in psoriasiform skin inflammation, which is characterized by epidermal thickening and interdigitation of epidermis and dermis, thus resembling papillomatosis (van der Fits et al., 2009). Cutaneous inflammation in the IMQ model appears to share many pathophysiologic pathways with (early) psoriasis plaque formation (Nestle et al., 2009). Hence, the immune cascade involved in this IMQ-induced psoriasis model hinges on the stimulation of DCs via TLR7 and 8, leading to activation of the IL-23−IL-17 axis with stimulation of T cells capable of IL-17 and IL-22 production (van der Fits et al., 2009; Cai et al., 2011; Pantelyushin et al., 2012; Tortola et al., 2012). The importance of IL-17 in psoriasis is further highlighted by the recent success of biologics targeting IL-17 in patients (Krueger, 2012; Leonardi et al., 2012; Papp et al., 2012).In addition to the immune system, keratinocytes have long been known to produce proinflammatory cytokines, including TNF and IL-1β, thus contributing to the inflammatory milieu in psoriatic skin plaques (Barker et al., 1991). Moreover, a publication examining the expression of IL-15 and IL-IL-15Rα on keratinocytes in vitro, as well as IL-15 and IL-15–binding sites in skin biopsies from psoriasis patients, suggested that keratinocytes might stimulate neighboring keratinocytes and immune cells by presenting IL-15 via membrane-bound IL-15Rα to these cells (Rückert et al., 2000). Recently, production of the proinflammatory IL-1 family member IL-36 by keratinocytes has been shown to play a role in inducing psoriasiform inflammation in the IMQ mouse model (Tortola et al., 2012). Furthermore, keratinocytes are known to secrete different antimicrobial peptides, including β-defensins, LL-37 cathelicidin, and S100 proteins. Some of these antimicrobial peptides are able to form complexes with self-DNA molecules, thereby leading to the activation of DCs, as has been shown for LL-37–DNA complexes stimulating plasmacytoid DCs via TLR9 engagement to produce IFN-α (Lande et al., 2007). Moreover, antimicrobial peptides exert chemotactic activities toward innate and adaptive immune cells. Thus, keratinocytes, through the production of antimicrobial peptides and proinflammatory cytokines, are contributing to cutaneous inflammation in immune defense, as well as in psoriasis (Nestle et al., 2009). However, whether keratinocytes or other stromal cells are involved in modulating or dampening inflammation in the skin is unknown.Here, we show that stromal cells, most notably keratinocytes in the skin, express high levels of IL-15Rα and release soluble IL-15Rα (sIL-15Rα) via proteolytic cleavage to suppress the inflammatory response in murine and human psoriasis. These data reveal a crucial role for stroma-derived sIL-15Rα in counter-regulating inflammation in this common chronic inflammatory disorder.     

β-Glucuronidase activity and mitochondrial dysfunction: the sites where flavonoid glucuronides act as anti-inflammatory agents

Epidemiological and experimental studies suggest that the consumption of flavonoid-rich diets decreases the risk of various chronic diseases such as cardiovascular diseases. Although studies on the bioavailability of flavonoids have been well-characterized, the tissue and cellular localizations underlying their biological mechanisms are largely unknown. The development and application of novel monoclonal antibodies revealed that macrophages could be the major target of dietary flavonoids in vivo. Using macrophage-like cell lines in vitro, we examined the molecular basis of the interaction between the macrophages and flavonoids, especially the glucuronide metabolites. We have found that extracellular β-glucuronidase secreted from macrophages is essential for the bioactivation of the glucuronide conjugates into the aglycone, and that the enzymatic activity, which requires an acidic pH, is promoted by the increased secretion of lactate in response to the mitochondrial dysfunction. This review describes our recent findings indicating the molecular mechanisms responsible for the anti-inflammatory activity of dietary flavonoids within the inflammation sites. We propose that the extracellular activity of β-glucuronidase associated with the status of the mitochondrial function in the target cells might be important biomarkers for the specific sites where the glucuronides of dietary flavonoids can act as anti-atherosclerotic and anti-inflammatory agents in vivo.     

A Transgenic Probiotic Secreting a Parasite Immunomodulator for Site-Directed Treatment of Gut Inflammation

New treatment strategies for inflammatory bowel disease are needed and parasitic nematode infections or application of helminth components improve clinical and experimental gut inflammation. We genetically modified the probiotic bacterium Escherichia coli Nissle 1917 to secrete the powerful nematode immunomodulator cystatin in the gut. This treatment was tested in a murine colitis model and on post-weaning intestinal inflammation in pigs, an outbred model with a gastrointestinal system similar to humans. Application of the transgenic probiotic significantly decreased intestinal inflammation in murine acute colitis, associated with increased frequencies of Foxp3⁺ Tregs, suppressed local interleukin (IL)-6 and IL-17A production, decreased macrophage inflammatory protein-1α/β, monocyte chemoattractant protein -1/3, and regulated upon activation, normal T-cell expressed, and secreted expression and fewer inflammatory macrophages in the colon. High dosages of the transgenic probiotic were well tolerated by post-weaning piglets. Despite being recognized by T cells, secreted cystatin did not lead to changes in cytokine expression or macrophage activation in the colon. However, colon transepithelial resistance and barrier function were significantly improved in pigs receiving the transgenic probotic and post-weaning colon inflammation was reduced. Thus, the anti-inflammatory efficiency of a probiotic can be improved by a nematode-derived immunoregulatory transgene. This treatment regimen should be further investigated as a potential therapeutic option for inflammatory bowel disease.     

Disabled homolog 2 controls macrophage phenotypic polarization and adipose tissue inflammation

Acute and chronic tissue injury results in the generation of a myriad of environmental cues that macrophages respond to by changing their phenotype and function. This phenotypic regulation is critical for controlling tissue inflammation and resolution. Here, we have identified the adaptor protein disabled homolog 2 (DAB2) as a regulator of phenotypic switching in macrophages. Dab2 expression was upregulated in M2 macrophages and suppressed in M1 macrophages isolated from both mice and humans, and genetic deletion of Dab2 predisposed macrophages to adopt a proinflammatory M1 phenotype. In mice with myeloid cell–specific deletion of Dab2 (Dab2^fl/fl Lysm-Cre), treatment with sublethal doses of LPS resulted in increased proinflammatory gene expression and macrophage activation. Moreover, chronic high-fat feeding exacerbated adipose tissue inflammation, M1 polarization of adipose tissue macrophages, and the development of insulin resistance in DAB2-deficient animals compared with controls. Mutational analyses revealed that DAB2 interacts with TNF receptor–associated factor 6 (TRAF6) and attenuates IκB kinase β–dependent (IKKβ-dependent) phosphorylation of Ser536 in the transactivation domain of NF-κB p65. Together, these findings reveal that DAB2 is critical for controlling inflammatory signaling during phenotypic polarization of macrophages and suggest that manipulation of DAB2 expression and function may hold therapeutic potential for the treatment of acute and chronic inflammatory disorders.     

Oral lichenoid tissue reactions: diagnosis and classification

The concept of lichenoid tissue reaction/interface dermatitis was introduced in dermatology to define a number of diverse inflammatory skin diseases linked together by the presence of common histopathological features. Similarly to the skin, the oral mucosa is affected by a variety of oral lichenoid lesions. Oral LTRs (OLTRs) include: oral lichen planus; oral lichenoid contact lesion; oral lichenoid drug reaction; oral lichenoid lesions of graft-versus-host disease; oral discoid lupus erythematosus; oral lesions of systemic lupus erythematosus; erythema multiforme; paraneoplastic pemphigus/paraneoplastic autoimmune multiorgan syndrome; chronic ulcerative stomatitis and lichen planus pemphigoid. Traditionally, diagnosis of OLTRs relies on clinical and histological correlation but in several instances this approach fails to provide a reliable diagnosis. Inclusion of molecular techniques may refine our ability to differentiate OLTRs.     

Anti-inflammatory activity of a water-soluble polysaccharide from the roots of purple sweet potato

In this study, a water-soluble polysaccharide was isolated from purple sweet potato roots. The in vitro and in vivo anti-inflammatory effects of the polysaccharide were evaluated by lipopolysaccharide (LPS)-induced inflammatory RAW264.7 macrophages and mice, respectively. The in vitro anti-inflammatory assay showed that the polysaccharide could effectively inhibit the overproduction of nitric oxide and pro-inflammatory cytokines (TNF-α, IL-1β, IL-6) while increasing the secretion of anti-inflammatory cytokine (IL-10). The in vivo anti-inflammatory assay revealed that mice administered with the polysaccharide showed higher IL-10, SOD, and T-AOC levels but lower TNF-α, IL-1β, IL-6 and MDA levels as compared to the LPS-treated model. Meanwhile, mice administered with the polysaccharide showed increased abundance of Lachnospiraceae, Lactobacillales and Parabacteroides but decreased amounts of Psychrobacter and Staphylococcus as compared to the LPS model group. Moreover, mice administered with polysaccharide showed enhanced production of short chain fatty acids by gut microbiota in the lipopolysaccharide-induced inflammatory mice. Our results suggested that the water-soluble polysaccharide from purple sweet potato roots could be utilized as a novel anti-inflammatory agent.

A water-soluble polysaccharide from purple sweet potato roots played anti-inflammatory roles by regulating inflammatory cytokines, gut microbiota and antioxidant defense system.     

Absence of Respiratory Burst in X-linked Chronic Granulomatous Disease Mice Leads to Abnormalities in Both Host Defense and Inflammatory Response to Aspergillus fumigatus

Mice with X-linked chronic granulomatous disease (CGD) generated by targeted disruption of the gp91^phox subunit of the NADPH–oxidase complex (X-CGD mice) were examined for their response to respiratory challenge with Aspergillus fumigatus. This opportunistic fungal pathogen causes infection in CGD patients due to the deficient generation of neutrophil respiratory burst oxidants important for damaging A. fumigatus hyphae. Alveolar macrophages from X-CGD mice were found to kill A. fumigatus conidia in vitro as effectively as alveolar macrophages from wild-type mice. Pulmonary disease in X-CGD mice was observed after administration of doses ranging from 10⁵ to 48 spores, none of which produced disease in wild-type mice. Higher doses produced a rapidly fatal bronchopneumonia in X-CGD mice, whereas progression of disease was slower at lower doses, with development of chronic inflammatory lesions. Marked differences were also observed in the response of X-CGD mice to the administration of sterilized Aspergillus hyphae into the lung. Within 24 hours of administration, X-CGD mice had significantly higher numbers of alveolar neutrophils and increased expression of the proinflammatory cytokines IL-1β and TNF-α relative to the responses seen in wild-type mice. By one week after administration, pulmonary inflammation was resolving in wild-type mice, whereas X-CGD mice developed chronic granulomatous lesions that persisted for at least six weeks. This is the first experimental evidence that chronic inflammation in CGD does not always result from persistent infection, and suggests that the clinical manifestations of this disorder reflect both impaired microbial killing as well as other abnormalities in the inflammatory response in the absence of a respiratory burst.     

Induction of high-affinity IgE receptor on lung dendritic cells during viral infection leads to mucous cell metaplasia

Respiratory viral infections are associated with an increased risk of asthma, but how acute Th1 antiviral immune responses lead to chronic inflammatory Th2 disease remains undefined. We define a novel pathway that links transient viral infection to chronic lung disease with dendritic cell (DC) expression of the high-affinity IgE receptor (FcεRIα). In a mouse model of virus-induced chronic lung disease, in which Sendai virus triggered a switch to persistent mucous cell metaplasia and airway hyperreactivity after clearance of replicating virus, we found that FceRIa^−/− mice no longer developed mucous cell metaplasia. Viral infection induced IgE-independent, type I IFN receptor–dependent expression of FcεRIα on mouse lung DCs. Cross-linking DC FcεRIα resulted in the production of the T cell chemoattractant CCL28. FceRIa^−/− mice had decreased CCL28 and recruitment of IL-13–producing CD4⁺ T cells to the lung after viral infection. Transfer of wild-type DCs to FceRIa^−/− mice restored these events, whereas blockade of CCL28 inhibited mucous cell metaplasia. Therefore, lung DC expression of FcεRIα is part of the antiviral response that recruits CD4⁺ T cells and drives mucous cell metaplasia, thus linking antiviral responses to allergic/asthmatic Th2 responses.     

Lichen planus

Lichen planus is an inflammatory mucocutaneous condition with characteristic violaceous polygonal flat-topped papules and plaques. Pruritus is often severe. Skin lesions may be disfiguring, and involvement of the oral mucosa or genital mucosa in severe cases may be debilitating. Oral lichen planus may predispose to the development of squamous cell carcinoma within lesions. Involvement of the scalp and the nails may also occur. While most cases of lichen planus are idiopathic, some may be caused by the ingestion of certain medications (e.g., gold, antimalarial agents, penicillamine, thiazide diuretics, beta blockers, nonsteroidal anti-inflammatory drugs, quinidine and angiotensin-converting enzyme inhibitors) or linked to hepatitis C virus infection. Patients with localized lichen planus are usually treated with potent topical steroids, while systemic steroids are used to treat patients with generalized lichen planus.     

Targeted deletion of Atg5 in intestinal epithelial cells promotes dextran sodium sulfate-induced colitis

Autophagy-associated genes have been identified as susceptible loci for inflammatory bowel disease. We investigated the role of a core autophagy factor, Atg5, in the development of dextran sodium sulfate (DSS)-induced colitis. Intestinal epithelial cell (IEC)-specific Atg5 gene deficient mice (Atg5^ΔIEC mice) were generated by cross of Atg5-floxed mice (Atg5^fl/fl) with transgenic mice expressing Cre-recombinase driven by the villin promotor. Mice were given three cycles of 1.5% DSS in drinking water for 5 days and regular water for 14 days over a 60-day period. The dysfunction of autophagy characterized by a marked accumulation of p62 protein, a substrate for autophagy degradation, was detected in epithelial cells in the non-inflamed and inflamed mucosa of inflammatory bowel disease patients. DSS-colitis was exacerbated in Atg5^ΔIEC mice compared to control Atg5^fl/fl mice. Phosphorylation of inositol-requiring transmembrane kinase/endonuclease1α (IRE1α), a sensor for endoplasmic reticulum stress, and c-Jun N-terminal kinase, a downstream target of IRE1α, were significantly enhanced in IECs in DSS-treated Atg5^ΔIEC mice. Accumulation of phosphorylated IRE1α was enhanced by the treatment with chloroquine, an autophagy inhibitor. Apoptotic IECs were more abundant in DSS-treated Atg5^ΔIEC mice. These findings suggest that Atg5 suppresses endoplasmic reticulum stress-induced apoptosis of IECs via the degradation of excess p-IRE1α.     

Agonistic induction of PPARγ reverses cigarette smoke–induced emphysema

The development of emphysema in humans and mice exposed to cigarette smoke is promoted by activation of an adaptive immune response. Lung myeloid dendritic cells (mDCs) derived from cigarette smokers activate autoreactive Th1 and Th17 cells. mDC-dependent activation of T cell subsets requires expression of the SPP1 gene, which encodes osteopontin (OPN), a pleiotropic cytokine implicated in autoimmune responses. The upstream molecular events that promote SPP1 expression and activate mDCs in response to smoke remain unknown. Here, we show that peroxisome proliferator–activated receptor γ (PPARG/Pparg) expression was downregulated in mDCs of smokers with emphysema and mice exposed to chronic smoke. Conditional knockout of PPARγ in APCs using Cd11c-Cre Pparg^flox/flox mice led to spontaneous lung inflammation and emphysema that resembled the phenotype of smoke-exposed mice. The inflammatory phenotype of Cd11c-Cre Pparg^flox/flox mice required OPN, suggesting an antiinflammatory mechanism in which PPARγ negatively regulates Spp1 expression in the lung. A 2-month treatment with a PPARγ agonist reversed emphysema in WT mice despite continual smoke exposure. Furthermore, endogenous PPARγ agonists were reduced in the plasma of smokers with emphysema. These findings reveal a proinflammatory pathway, in which reduced PPARγ activity promotes emphysema, and suggest that targeting this pathway in smokers could prevent and reverse emphysema.     

Artesunate attenuates inflammatory injury and inhibits the NF-κB pathway in a mouse model of cerebral ischemia

ObjectiveInflammation is an important factor in the pathological process of cerebral ischemia. Artesunate exhibits a broad range of anti-inflammatory properties in many diseases. We investigated the potential protective effect of artesunate against cerebral ischemia and the related mechanisms.MethodsMice were divided into distal middle cerebral artery occlusion (dMCAO), sham, low dose, and high dose groups and subjected to dMCAO, except for the sham group. The low and high dose groups were administered artesunate (15 and 30 mg/kg), and the neuroprotective effects were analyzed by evaluating infarct volumes and neurological deficits. Microglial activation and neutrophil infiltration were evaluated by immunofluorescence, immunohistochemical staining, and western blotting. Inflammatory mediators were measured by enzyme-linked immunosorbent assays. Nuclear factor (NF)-κB nuclear translocation was detected by immunofluorescence and western blotting.ResultsCompared with the dMCAO group, artesunate significantly improved neurological deficit scores and infarct volumes and ameliorated inflammation by reducing neutrophil infiltration, suppressing microglial activation, and downregulating tumor necrosis factor-α and interleukin-1β expression. Furthermore, artesunate inhibited nuclear translocation of NF-κB and inhibitor protein α proteolysis.ConclusionsArtesunate protected against inflammatory injury by reducing neutrophil infiltration and microglial activation, suppressing inflammatory cytokines, and inhibiting the NF-κB pathway. Therefore, artesunate is a potential ischemic stroke treatment.     

Long Noncoding RNA Arid2-IR Is a Novel Therapeutic Target for Renal Inflammation

Increasing evidence shows that microRNAs play an important role in kidney disease. However, functions of long noncoding RNAs (lncRNAs) in kidney diseases remain undefined. We have previously shown that TGF-β1 plays a diverse role in renal inflammation and fibrosis and Smad3 is a key mediator in this process. In this study, we used RNA-sequencing to identify lncRNAs related to renal inflammation and fibrosis in obstructive nephropathy induced in Smad3 wild-type and knockout mice. We found that Arid2-IR was a Smad3-associated lncRNA as a Smad3 binding site was found in the promoter region of Arid2-IR and deletion of Smad3 abolished upregulation of Arid2-IR in the diseased kidney. In vitro knockdown of Arid2-IR from tubular epithelial cells produced no effect on TGF-β-induced Smad3 signaling and fibrosis but inhibited interleukin-1β-stimulated NF-κB-dependent inflammatory response. In contrast, overexpression of Arid2-IR promoted interleukin-1β-induced NF-κB signaling and inflammatory cytokine expression without alteration of TGF-β1-induced fibrotic response. Furthermore, treatment of obstructed kidney with Arid2-IR shRNA blunted NF-κB-driven renal inflammation without effect on TGF-β/Smad3-mediated renal fibrosis. Thus, Arid2-IR is a novel lncRNA that functions to promote NF-κB-dependent renal inflammation. Blockade of Arid2-IR may represent a novel and specific therapy for renal inflammatory disease.