Excessive Tissue Damage Research Articles

Type 2 innate lymphoid cells in the induction and resolution of tissue inflammation.

Type 2 immunity against pathogens is tightly regulated to ensure appropriate inflammatory responses that clear infection and prevent excessive tissue damage. Recent research has shown that type 2 innate lymphoid cells (ILC2s) contribute to steady-state tissue integrity and exert tissue-specific functions. However, upon exposure to inflammatory stimuli, they also initiate and amplify type 2 inflammation by inducing mucus production, eosinophilia, and Th2 differentiation. In this review, we discuss the regulation of ILC2 activation by transcription factors and metabolic pathways, as well as by extrinsic signals such as cytokines, lipid mediators, hormones, and neuropeptides. We also review recent discoveries about ILC2 plasticity and heterogeneity in different tissues, as revealed partly through single-cell RNA sequencing of transcriptional responses to various stimuli. Understanding the tissue-specific pathways that regulate ILC2 diversity and function is a critical step in the development of potential therapies for allergic diseases.

The challenge of implant integration in partial meniscal replacement: an experimental study on a silk fibroin scaffold in sheep

PurposeTo restore meniscal function after excessive tissue damage, a silk fibroin implant for partial meniscal replacement was developed and investigated in an earlier sheep model. After 6 months implantation, it showed promising results in terms of chondroprotection and biocompatibility. To improve surgical fixation, the material was subjected to optimisation and a fibre mesh was integrated into the porous matrix. The aim of the study was the evaluation of this second generation of silk fibroin implants in a sheep model.MethodsNine adult merino sheep received subtotal meniscal replacement using the silk fibroin scaffold. In nine additional animals, the defect was left untreated. Sham surgery was performed in another group of nine animals. After 6 months of implantation macroscopic, biomechanical and histological evaluations of the scaffold, meniscus, and articular cartilage were conducted.ResultsMacroscopic evaluation revealed no signs of inflammation of the operated knee joint and most implants were located in the defect. However, there was no solid connection to the remaining peripheral meniscal rim and three devices showed a radial rupture at the middle zone. The equilibrium modulus of the scaffold increased after 6 months implantation time as identified by biomechanical testing (before implantation 0.6 ± 0.3 MPa; after implantation: 0.8 ± 0.3 MPa). Macroscopically and histologically visible softening and fibrillation of the articular cartilage in the meniscectomy- and implant group were confirmed biomechanically by indentation testing of the tibial cartilage.ConclusionsIn the current study, biocompatibility of the silk fibroin scaffold was reconfirmed. The initial mechanical properties of the silk fibroin implant resembled native meniscal tissue. However, stiffness of the scaffold increased considerably after implantation. This might have prevented integration of the device and chondroprotection of the underlying cartilage. Furthermore, the increased stiffness of the material is likely responsible for the partial destruction of some implants. Clinically, we learn that an inappropriate replacement device might lead to similar cartilage damage as seen after meniscectomy. Given the poor acceptance of the clinically available partial meniscal replacement devices, it can be speculated that development of a total meniscal replacement device might be the less challenging option.

Host–Parasite Interactions Promote Disease Tolerance to Intestinal Helminth Infection

Parasitic helminths are among the most pervasive pathogens of the animal kingdom. To complete their life cycle, these intestinal worms migrate through host tissues causing significant damage in their wake. As a result, infection can lead to malnutrition, anemia and increased susceptibility to co-infection. Despite repeated deworming treatment, individuals living in endemic regions remain highly susceptible to re-infection by helminths, but rarely succumb to excessive tissue damage. The chronicity of infection and inability to resist numerous species of parasitic helminths that have co-evolved with their hosts over millenia suggests that mammals have developed mechanisms to tolerate this infectious disease. Distinct from resistance where the goal is to destroy and eliminate the pathogen, disease tolerance is an active process whereby immune and structural cells restrict tissue damage to maintain host fitness without directly affecting pathogen burden. Although disease tolerance is evolutionary conserved and has been well-described in plant systems, only recently has this mode of host defense, in its strictest sense, begun to be explored in mammals. In this review, we will examine the inter- and intracellular networks that support disease tolerance during enteric stages of parasitic helminth infection and why this alternative host defense strategy may have evolved to endure the presence of non-replicating pathogens and maintain the essential functions of the intestine.

Newcastle disease virus infection triggers HMGB1 release to promote the inflammatory response

High mobility group box 1 (HMGB1) is a key member of the “danger associated molecular patterns” (DAMPs) which plays important roles in systemic inflammation and has a pathogenic role in infectious diseases like viral or bacterial infections. Newcastle disease virus (NDV) infection is proved to cause intense inflammatory responses that result in excessive cellular apoptosis and tissue damage, but the function of HMGB1 in NDV-induced cytokine storm has not been elucidated. Here, we report that HMGB1 is a significant inflammation factor in NDV infection. HMGB1 is widely distributed in chicken tissues, and the secretion of it was induced by NDV infection both in DF-1 and A549 cells. Moreover, inhibiting the secretion of HMGB1, NDV replication was not significantly reduced, but it is involved in NDV-induced NF-κB activation and the inflammatory response. Further investigation showed that HMGB1 promotes inflammatory cytokine production through the RAGR, TLR2, and TLR4 receptors. HMGB1-RAGE interaction also takes parts in activation of ERK1/2 and JNK induced by NDV infection. Neutralizing HMGB1 in vivo, chicken viability was increased. Pathological changes and inflammatory cytokines expression were reduced under NDV infection, which further confirmed the pathogenic roles of HMGB1 in inflammatory responses. Thus, our findings show that HMGB1 contributes to the inflammatory cytokine storm induced by NDV infection, which played a critical role in viral pathogenesis.

Interaction of PVR/PVRL2 with TIGIT/DNAM-1 as a novel immune checkpoint axis and therapeutic target in cancer.

Avoiding immune surveillance and inducing a tumor-promoting inflammatory milieu found entry into the new generation of the hallmarks of cancer. Cancer cells hijack immune mechanisms which physiologically protect the body from the development of autoimmune diseases and excessive tissue damage during inflammation by downregulating immune responses. This is frequently achieved by upregulation of immune checkpoints. Therefore, the blocking of immune checkpoint ligand-receptor interactions can reinstall the immune systems capability to fight cancer cells as shown for CTLA4 and PD-1 inhibitors in a clinical setting. Newly described checkpoint antigens are currently under investigation in cancer immunotherapy. Preclinical data emphasize the immune checkpoint axis TIGIT-PVR/PVRL2 as very promising target. This axis includes additional receptors such as DNAM-1, CD96, and CD112R. In this review, we discuss the recent findings of the relevance of this complex receptor ligand system in hematologic and solid cancers. Emphasis is also laid on the discussion of potential combinations with other immunotherapeutic approaches.

TSG-6 attenuates inflammation-induced brain injury via modulation of microglial polarization in SAH rats through the SOCS3/STAT3 pathway

BackgroundAn acute and drastic inflammatory response characterized by the production of inflammatory mediators is followed by stroke, including SAH. Overactivation of microglia parallels an excessive inflammatory response and worsened brain damage. Previous studies indicate that TSG-6 has potent immunomodulatory and anti-inflammatory properties. This study aimed to evaluate the effects of TSG-6 in modulating immune reaction and microglial phenotype shift after experimental SAH.MethodsThe SAH model was established by endovascular puncture method for Sprague–Dawley rats (weighing 280–320 g). Recombinant human protein and specific siRNAs for TSG-6 were exploited in vivo. Brain injury was assessed by neurologic scores, brain water content, and Fluoro-Jade C (FJC) staining. Microglia phenotypic status was evaluated and determined by Western immunoblotting, quantitative real-time polymerase chain reaction (qPCR) analyses, flow cytometry, and immunofluorescence labeling.ResultsSAH induced significant inflammation, and M1-dominated microglia polarization increased expression of TSG-6 and neurological dysfunction in rats. rh-TSG-6 significantly ameliorated brain injury, decreased proinflammatory mediators, and skewed microglia towards a more anti-inflammatory property 24-h after SAH. While knockdown of TSG-6 further induced detrimental effects of microglia accompanied with more neurological deficits, the anti-inflammation effects of rh-TSG-6 were associated with microglia phenotypic shift by regulating the level of SOCS3/STAT3 axis.ConclusionsTSG-6 exerted neuroprotection against SAH-induced EBI in rats, mediated in part by skewing the balance of microglial response towards a protective phenotype, thereby preventing excessive tissue damage and improving functional outcomes. Our findings revealed the role of TSG-6 in modulating microglial response partially involved in the SOCS3/STAT3 pathway and TSG-6 may be a promising therapeutic target for the treatment of brain injury following SAH.

Hemato-Biochemical and Histopathological Changes Caused by Coccidiosis in broilers

The aim of present work is to determine the Hematological, biochemical and histopathological alterations caused by coccidiosis in broiler chickens from an outbreak of bloody coccidiosis in a flock. The study was conducted on Al bahrani field for commercial broiler in Al Najaf province-Iraq.Blood samples were collected from jugular vein into EDTA tubes for hematological value and plain tube for biochemical value during October 2017 . Result showed that the Anemia caused by the coccidian was characterized by a decreased number of red blood cells (RBC) and decreased packed cell volume (PCV). Differential leukocyte counts revealed to increase in monocytes, lymphocytes, heterophil and eosinophil. Also, Serum biochemical analysis showed decreases in alanine aminotransferase (ALT) and aspartate aminotransferase (AST), and a marked increase in alkaline phosphatase (ALP) activities. On the other hand, Histopathological examinations of the affected caeca also demonstrated excessive tissue damage, hemorrhage, the crypt cells were highly invaded with the developmental stages of E. tenella schizonts and gametocytes that their morphology is practically missing. In conclusions the present study revealed changes in the hematology, blood chemistry and histopathology of broilers caused by E. tenella and E.brunetti.

A nonlinear homogenized finite element analysis of the primary stability of the bone-implant interface.

Stability of an implant is defined by its ability to undergo physiological loading-unloading cycles without showing excessive tissue damage and micromotions at the interface. Distinction is usually made between the immediate primary stability and the long-term, secondary stability resulting from the biological healing process. The aim of this research is to numerically investigate the effect of initial implantation press-fit, bone yielding, densification and friction at the interface on the primary stability of a simple bone-implant system subjected to loading-unloading cycles. In order to achieve this goal, human trabecular bone was modeled as a continuous, elasto-plastic tissue with damage and densification, which material constants depend on bone volume fraction and fabric. Implantation press-fit related damage in the bone was simulated by expanding the drilled hole to the outer contour of the implant. The bone-implant interface was then modeled with unilateral contact with friction. The implant was modeled as a rigid body and was subjected to increasing off-axis loading cycles. This modeling approach is able to capture the experimentally observed primary stability in terms of initial stiffness, ultimate force and progression of damage. In addition, it is able to quantify the micromotions around the implant relevant for bone healing and osseointegration. In conclusion, the computationally efficient modeling approach used in this study provides a realistic structural response of the bone-implant interface and represents a powerful tool to explore implant design, implantation press-fit and the resulting risk of implant failure under physiological loading.

Platelet-monocyte interaction in Mycobacterium tuberculosis infection

The immune effects of platelets and platelet-leukocyte aggregation are increasingly recognized. We studied the occurrence of platelet-monocyte aggregation (PMA) in patients with pulmonary tuberculosis (TB), the processes underlying PMA and consequences for cytokine responses.In a cross-sectional study involving 65 Tanzanian TB patients in different phases of treatment and 29 healthy controls, TB patients had a significantly higher PMA. This increased PMA in TB patients was associated with increased monocyte CCR5, CD16 expression and PF4, but not with increased membrane-expressed or soluble P-selectin expression. These findings were confirmed in vitro: whereas incubation of whole blood with Mycobacterium tuberculosis (Mtb) did not activate platelets, monocytes became activated with higher CD11b, CD16 and CCR5 expression, but this was independent of platelet-monocyte interaction. Still, platelets had an anti-inflammatory effect on cytokine responses as peripheral blood mononuclear cells (PBMC) incubated with Mtb in the presence of platelets produced less interleukin (IL)-1β, tumor necrosis factor-α, IL-6 and interferon-γ and more IL-10.In conclusion, increased PMA during TB infection is caused by monocyte and not platelet activation. By counteracting the Mtb-induced pro-inflammatory leukocyte response, platelets may protect against excessive tissue damage, but may also compromise the production of protective cytokines, such as IFNƴ and TNFα.

Suboptimal stimulation with staphylococcal enterotoxin C1 induces immunosuppressive CD4+CD25+ regulatory T cells by differential expression of FOXP3 isoforms

Abstract Regulatory T cells (Tregs) play an important role in maintaining immune homeostasis and preventing excessive tissue damage upon immune activation. However, pathogens could exploit Tregs for their successful pathogenesis. We demonstrated that immunosuppressive CD4+CD25+FOXP3+ Tregs were induced by staphylococcal enterotoxin (SE) produced by an important human pathogen, Staphylococcus aureus. CD4+CD25+FOXP3+ T cells were induced from stimulation with SEC1 at a high (1 μg/ml) and low (1 ng/ml) concentrations that induced optimal stimulation and suboptimal stimulation, respectively. However, CD4+CD25+FOXP3+ T cells induced from suboptimal stimulation were functionally immunosuppressive, not from optimal stimulation. Immunosuppressive CD4+CD25+FOXP3+ T cells induced from suboptimal stimulation showed typical Treg surface markers such as CTLA-4, GITR, TNFR2, and CD45RO and produced immunomodulatory cytokines such as TGF-β and IL-10. However, suppression was mainly mediated by galectin-1 in a contact-dependent manner. We found that CD4+CD25+ Tregs from suboptimal stimulation highly express FOXP3 isoform lacking exon 2 (ΔE2) and partially lacking exon3 (ΔpE3) preferably localized to the nucleus, compared to those from optimal stimulation. Lentiviral transduction of FOXP3 isoforms (full length, ΔE2, ΔpE3) to Jurkat T cells did not result in immunosuppressive function. By contrast, when cultured in the media generated from suboptimal T cell stimulation, transduced Jurkat T cells became more immunosuppressive in an order of ΔE2 ΔpE3, and full length FOXP3. These results suggest that soluble factors generated from suboptimal T cell proliferation play an important role in induction of immunosuppressive Tregs.

Gut microbiota enhances neutrophil resolution in immunocompromised hosts to improve response to pneumococcal pneumonia.

Abstract Streptococcus pneumoniae is a major cause of disease and death worldwide, particularly in neonatal, elderly, and immunodeficient patients. We examined the impact of the gut microbiota on lung disease (known as the gut-lung axis) using traditional immunocompetent as well as novel immunocompromised mouse models of S. pneumoniae lung infection. Adaptive immunity against S. pneumoniae depends largely on T-independent II (TI-II) antibodies against the bacterial polysaccharide capsule. We found that colonization with the gut commensal Segmented Filamentous Bacteria (SFB) increased anti-S. pneumoniae TI-II antibodies, but did not further enhance protection against S. pneumoniae in wild type mice. Indeed, basal B cell activity in the absence of SFB colonization was sufficient to provide essential protection against S. pneumoniae. However, in adaptive immune-compromised mice, we demonstrated a gut-lung axis of communication, as SFB colonization modulated the innate immune response to enhance protection against S. pneumoniae lung infection. Neutrophils are important first responders during pneumonia, but proper neutrophil resolution is essential to prevent excessive tissue damage. We found that SFB colonization led to more efficient clearance of lung neutrophils at 3 days after infection, which correlated with a decrease in CD47, a transmembrane glycoprotein that inhibits clearance of apoptotic cells, on lung neutrophils in SFB+ immunocompromised mice. This accompanied a shift in lung neutrophils from CD18hiCD62L−/lo inflammatory neutrophils to CD18−/loCD62Lhi pro-resolution neutrophils. These data demonstrate that a gut commensal modulates the innate immune response to enhance protection against a lung infection.

15-epi-Lipoxin A4, Resolvin D2, and Resolvin D3 Induce NF-κB Regulators in Bacterial Pneumonia.

Specialized proresolving mediators (SPMs) decrease NF-κB activity to prevent excessive tissue damage and promote the resolution of acute inflammation. Mechanisms for NF-κB regulation by SPMs remain to be determined. In this study, after LPS challenge, the SPMs 15-epi-lipoxin A4 (15-epi-LXA4), resolvin D1, resolvin D2, resolvin D3, and 17-epi-resolvin D1 were produced in vivo in murine lungs. In LPS-activated human bronchial epithelial cells, select SPMs increased expression of the NF-κB regulators A20 and single Ig IL-1R-related molecule (SIGIRR). Of interest, 15-epi-LXA4 induced A20 and SIGIRR in an lipoxin A4 receptor/formyl peptide receptor 2 (ALX/FPR2) receptor-dependent manner in epithelial cells and in murine pneumonia. This SPM regulated NF-κB-induced cytokines to decrease pathogen-mediated inflammation. In addition to dampening lung inflammation, surprisingly, 15-epi-LXA4 also enhanced pathogen clearance with increased antimicrobial peptide expression. Taken together, to our knowledge these results are the first to identify endogenous agonists for A20 and SIGIRR expression to regulate NF-κB activity and to establish mechanisms for NF-κB regulation by SPMs for pneumonia resolution.

Biological Activities of Heteropyxis natalensis Against Micro-Organisms Involved in Oral Infections.

The use of complementary and alternative medicine from plants in South Africa, as in the rest of the world, continues to increase. Heteropyxis natalensis, known as the Lavender tree, is indigenous to South Africa and is traditionally used for oral care. The ethanolic extract, of the leaves and twigs, of H. natalensis was investigated for antimicrobial activity against selected oral microorganisms. Actinomyces israelii was found to be the most sensitive oral microorganism to the extract, with a minimum inhibitory concentration (MIC) of 0.88 mg/ml and an MIC of 2.6 mg/ml against Streptococcus mutans. Five known compounds were identified from the ethanolic extract of H. natalensis. The compounds were identified as aurentiacin A (1), cardamomin (2), 5-hydroxy-7-methoxy-6-methylflavanone (3), quercetin (4) and 3,5,7-trihydroxyflavan (5). The MICs of the compounds 1 and 4 were found to be 0.06 mg/ml and 1 mg/ml, respectively, against A. israelii. The cytotoxicity, acute and sub-acute toxicity in pre-clinical studies were also determined for H. natalensis. The extract showed moderate cytotoxicity (35.56 ± 0.16 μg/ml) on human monocyte cells. The acute and sub-acute toxicity analysis of H. natalensis indicated the NOEL (no-observed-effect level) at 200 mg/kg. Interleukin-8 (IL-8) is a chemokine that stimulates the recruitment of leukocytes. A significant reduction of IL-8 production by macrophage cells was observed when exposed to the extract of H. natalensis. It is possible that H. natalensis can prevent excessive tissue damage in periodontal diseases through its reduction of inflammation. Enzymatic bioanalysis of lactic and acetic acid production from Streptococcus mutans and Lactobacillus paracasei was done. A reduction in the acid production from each bacterium was observed on exposure to the extract of H. natalensis. Consequently, this increased the pH, which could possibly reduce the demineralization of enamel which may help prevent the formation of dental caries. In addition the extract may be considered for preventing periodontal diseases.

Targeting Myeloid-Derived Suppressor Cells to Bypass Tumor-Induced Immunosuppression.

The immune system has many sophisticated mechanisms to balance an extensive immune response. Distinct immunosuppressive cells could protect from excessive tissue damage and autoimmune disorders. Tumor cells take an advantage of those immunosuppressive mechanisms and establish a strongly immunosuppressive tumor microenvironment (TME), which inhibits antitumor immune responses, supporting the disease progression. Myeloid-derived suppressor cells (MDSC) play a crucial role in this immunosuppressive TME. Those cells represent a heterogeneous population of immature myeloid cells with a strong immunosuppressive potential. They inhibit an antitumor reactivity of T cells and NK cells. Furthermore, they promote angiogenesis, establish pre-metastatic niches, and recruit other immunosuppressive cells such as regulatory T cells. Accumulating evidences demonstrated that the enrichment and activation of MDSC correlated with tumor progression, recurrence, and negative clinical outcome. In the last few years, various preclinical studies and clinical trials targeting MDSC showed promising results. In this review, we discuss different therapeutic approaches on MDSC targeting to overcome immunosuppressive TME and enhance the efficiency of current tumor immunotherapies.

Staphylococcus aureus triggers a shift from influenza virus-induced apoptosis to necrotic cell death.

Superinfections with Staphylococcus aureus are a major complication of influenza disease, causing excessive inflammation and tissue damage. This enhanced cell-damaging effect is also observed in superinfected tissue cultures, leading to a strong decrease in overall cell viability. In our analysis of the underlying molecular mechanisms, we observed that, despite enhanced cell damage in superinfection, S. aureus did not increase but rather inhibited influenza virus (IV)-induced apoptosis in cells on the level of procaspase-8 activation. This apparent contradiction was solved when we observed that S. aureus mediated a switch from apoptosis to necrotic cell death of IV-infected cells, a mechanism that was dependent on the bacterial accessory gene regulator ( agr) locus that promotes bacterial survival and spread. This so far unknown action may be a bacterial strategy to enhance dissemination of intracellular S. aureus and may thereby contribute to increased tissue damage and severity of disease.-Van Krüchten, A., Wilden, J. J., Niemann, S., Peters, G., Löffler, B., Ludwig, S., Ehrhardt, C. Staphylococcus aureus triggers a shift from influenza virus-induced apoptosis to necrotic cell death.

Assessment of test method variables for in vitro skin irritation testing of medical device extracts

Skin irritation is an important component of the biological safety evaluation of medical devices. This testing has typically been performed using in vivo models. However, in an effort to reduce the need for in vivo testing, alternative methods for assessing skin irritation potential in vitro have been developed using a Reconstructed Human Epidermis (RhE) model. During the development of the protocol for the round robin validation of in vitro irritation testing for medical device extracts, it became clear that there were three points in the procedure where different options may be validated within each laboratory for routine testing: sample exposure time (18 vs 24h), SDS positive control concentration, and cytokine (IL-1α) release testing. The goal of our study was to evaluate the effect of these variables. EpiDerm™ tissues were exposed to extracts of three plain polymer samples, and four polymers embedded with known irritant chemicals. Exposures were performed for 18 and 24h. Resulting tissue viability was assessed by MTT reduction and IL-1α release was assessed by ELISA. Testing was also performed using various concentrations of SDS ranging from 0.5 to 1% (w/v). Overall, results were similar for samples tested and 18 and 24h, but the 18h exposure time has the potential to have an impact on the results of some sample types. IL-1α testing was shown to be useful to clarify conflicting tissue viability results. Use of a lower concentration of SDS as a positive control can help prevent issues that arise from excessive tissue damage often caused by 1% SDS.

Disease Tolerance Mediated by Phosphorylated Indoleamine-2,3 Dioxygenase Confers Resistance to a Primary Fungal Pathogen.

Resistance to primary fungal pathogens is usually attributed to the proinflammatory mechanisms of immunity conferred by interferon-γ activation of phagocytes that control microbial growth, whereas susceptibility is attributed to anti-inflammatory responses that deactivate immunity. This study challenges this paradigm by demonstrating that resistance to a primary fungal pathogen such as Paracoccidiodes brasiliensis can be mediated by disease tolerance, a mechanism that preserves host fitness instead of pathogen clearance. Among the mechanisms of disease tolerance described, a crucial role has been ascribed to the enzyme indoleamine-2,3 dioxygenase (IDO) that concomitantly controls pathogen growth by limiting tryptophan availability and reduces tissue damage by decreasing the inflammatory process. Here, we demonstrated in a pulmonary model of paracoccidioidomycosis that IDO exerts a dual function depending on the resistant pattern of hosts. IDO activity is predominantly enzymatic and induced by IFN-γ signaling in the pulmonary dendritic cells (DCs) from infected susceptible (B10.A) mice, whereas phosphorylated IDO (pIDO) triggered by TGF-β activation of DCs functions as a signaling molecule in resistant mice. IFN-γ signaling activates the canonical pathway of NF-κB that promotes a proinflammatory phenotype in B10.A DCs that control fungal growth but ultimately suppress T cell responses. In contrast, in A/J DCs IDO promotes a tolerogenic phenotype that conditions a sustained synthesis of TGF-β and expansion of regulatory T cells that avoid excessive inflammation and tissue damage contributing to host fitness. Therefore, susceptibility is unexpectedly mediated by mechanisms of proinflammatory immunity that are usually associated with resistance, whereas genetic resistance is based on mechanisms of disease tolerance mediated by pIDO, a phenomenon never described in the protective immunity against primary fungal pathogens.

Nitric Oxide Modulates Macrophage Responses to Mycobacterium tuberculosis Infection through Activation of HIF-1α and Repression of NF-κB.

IFN-γ is essential for control of Mycobacterium tuberculosis infection in vitro and in vivo. However, the mechanisms by which IFN-γ controls infection remain only partially understood. One of the crucial IFN-γ target genes required for control of M. tuberculosis is inducible NO synthase (iNOS). Although NO produced by iNOS is thought to have direct bactericidal activity against M. tuberculosis, the role of NO as a signaling molecule has been poorly characterized in the context M. tuberculosis infection. In this study, we found that iNOS broadly regulates the macrophage transcriptome during M. tuberculosis infection, activating antimicrobial pathways while also limiting inflammatory cytokine production. The transcription factor hypoxia inducible factor-1α (HIF-1α) was recently shown to be critical for IFN-γ-mediated control of M. tuberculosis infection. We found that HIF-1α function requires NO production, and that HIF-1α and iNOS are linked by a positive feedback loop that amplifies macrophage activation. Furthermore, we found that NO inhibits NF-κB activity to prevent hyperinflammatory responses. Thus, NO activates robust microbicidal programs while also limiting damaging inflammation. IFN-γ signaling must carefully calibrate an effective immune response that does not cause excessive tissue damage, and this study identifies NO as a key player in establishing this balance during M. tuberculosis infection.

MicroRNA-146a governs fibroblast activation and joint pathology in arthritis

Synovial fibroblasts are key cells orchestrating the inflammatory response in arthritis. Here we demonstrate that loss of miR-146a, a key epigenetic regulator of the innate immune response, leads to increased joint destruction in a TNF-driven model of arthritis by specifically regulating the behavior of synovial fibroblasts. Absence of miR-146a in synovial fibroblasts display a highly deregulated gene expression pattern and enhanced proliferation in vitro and in vivo. Deficiency of miR-146a induces deregulation of tumor necrosis factor (TNF) receptor associated factor 6 (TRAF6) in synovial fibroblasts, leading to increased proliferation. In addition, loss of miR-146a shifts the metabolic state of fibroblasts towards glycolysis and augments the ability of synovial fibroblasts to support the generation of osteoclasts by controlling the balance of osteoclastogenic regulatory factors receptor activator of NF-κB ligand (RANKL) and osteoprotegerin (OPG). Bone marrow transplantation experiments confirmed the importance of miR-146a in the radioresistant mesenchymal compartment for the control of arthritis severity, in particular for inflammatory joint destruction. This study therefore identifies microRNA-146a as an important local epigenetic regulator of the inflammatory response in arthritis. It is a central element of an anti-inflammatory feedback loop in resident synovial fibroblasts, who are orchestrating the inflammatory response in chronic arthritis. MiR-146a restricts their activation, thereby preventing excessive tissue damage during arthritis.

Bap180/Baf180 is required to maintain homeostasis of intestinal innate immune response in Drosophila and mice.

Immune homeostasis is a prerequisite to protective immunity against gastrointestinal infections. In Drosophila, immune deficiency (IMD) signalling (tumour necrosis factor receptor/interleukin-1 receptor, TNFR/IL-1R in mammals) is indispensable for intestinal immunity against invading bacteria. However, how this local antimicrobial immune response contributes to inflammatory regulation remains poorly defined. Here, we show that flies lacking intestinal Bap180 (a subunit of the chromatin-remodelling switch/sucrose non-fermentable (SWI/SNF) complex) are susceptible to infection as a result of hyper-inflammation rather than bacterial overload. Detailed analysis shows that Bap180 is induced by the IMD-Relish response to both enteropathogenic and commensal bacteria. Upregulated Bap180 can feed back to restrain overreactive IMD signalling, as well as to repress the expression of the pro-inflammatory gene eiger (TNF), a critical step to prevent excessive tissue damage and elongate the lifespan of flies, under pathological and physiological conditions, respectively. Furthermore, intestinal targeting of Baf180 renders mice susceptible to a more aggressive infectious colitis caused by Citrobacter rodentium. Together, Bap180 and Baf180 serve as a conserved transcriptional repressor that is critical for the maintenance of innate immune homeostasis in the intestines.