Acute and chronic inflammatory responses in the lung are associated with the accumulation of large quantities of immune and structural cells undergoing apoptosis, which need to be engulfed by ...phagocytes in a process called ‘efferocytosis’. Apoptotic cell recognition and removal from the lung is mediated predominantly by airway macrophages, though immature dendritic cells and non-professional phagocytes, such as epithelial cells and mesenchymal cells, can also display this function. Efficient clearance of apoptotic cells from the airways is essential for successful resolution of inflammation and the return to lung homeostasis. Disruption of this process leads to secondary necrosis of accumulating apoptotic cells, release of necrotic cell debris and subsequent uncontrolled inflammatory activation of the innate immune system by the released ‘damage associated molecular patterns’ (DAMPS). To control the duration of the immune response and prevent autoimmune reactions, anti-inflammatory signalling cascades are initiated in the phagocyte upon apoptotic cell uptake, mediated by a range of receptors that recognise specific phospholipids or proteins externalised on, or secreted by, the apoptotic cell. However, prolonged activation of apoptotic cell recognition receptors, such as the family of receptor tyrosine kinases Tyro3, Axl and MerTK (TAM), may delay or prevent inflammatory responses to subsequent infections. In this review, we will discuss recent advances in our understanding of the mechanism controlling apoptotic cell recognition and removal from the lung in homeostasis and during inflammation, the contribution of defective efferocytosis to chronic inflammatory lung diseases, such as chronic obstructive pulmonary disease, asthma and cystic fibrosis, and implications of the signals triggered by apoptotic cells in the susceptibility to pulmonary microbial infections.
Pathogens have developed sophisticated strategies to evade the immune response, among which manipulation of host cellular epigenetic mechanisms plays a prominent role. In the last decade, modulation ...of histone acetylation in host cells has emerged as an efficient strategy of bacterial immune evasion. Virulence factors and metabolic products of pathogenic microorganisms alter expression and activity of histone acetyltransferases (HATs) and histone deacetylases (HDACs) to suppress transcription of host defense genes through epigenetic changes in histone acetylation marks. This new avenue of pathogen-host interactions is particularly important in light of introduction of HDAC inhibitors into clinical practice. Considerable effort is currently being applied to better understand the effects of HDAC inhibitors on the quality of immune responses to pathogens and to characterize the therapeutic potential of these compounds in microbial infections. In this review, we will discuss the recently discovered mechanisms utilized by bacteria to facilitate their survival within infected hosts through subversion of the host acetylation system and the effects of acetylation modulators, including HDAC inhibitors and bromodomain-containing BET protein inhibitors, on innate immune responses against microbial pathogens. Integration of these two lines of experimental evidence provides critical information on the perspectives of epigenetic therapies targeting protein acetylation in infectious diseases.
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► Calcium carbonate biodeposition method contributed to decrease in water absorption of recycled concrete aggregate. ► Better efficiency was obtained for finer aggregate fraction and ...in the case of aggregate of lower quality. ► Efficiency of calcium chloride and whey as culture media was confirmed. ► Observations under SEM showed covering aggregate grains with calcium carbonate.
A growing demand for raw materials leads to danger of premature depletion of the natural sources. An alternative is to use by-products, provided their quality is improved. The paper presents surface modification of recycled aggregate concrete using biodeposition involving a method employing Sporosarcina pasteurii (Bacillus pasteurii) bacteria. It was possible to obtain reduction in water absorption of aggregate, the effect was more visible in case of finer fractions and for aggregates originating from inferior quality concrete. Calcium chloride was used for precipitation of calcium carbonate, while culture medium consisting of beef extract, peptone and urea was used for cultivation of microorganisms. In addition, whey, ecologically dangerous by-product from dairy industry was found to be effective as a culture medium. Presence of calcium carbonate crystals covering aggregate grains was confirmed by observations under scanning electron microscope. In the perspective, the proposed method, upon appropriate improvements, seems worthwhile due to ecological and technological reasons.
For complete utilization of construction and demolition (C&D) waste, an investigation of all size fractions of C&D waste generated during the recycling process should be conducted. In this work, the ...effects of three recycled concrete materials with different sizes (recycled coarse aggregate (RCA) with a size of 4.75-25 mm, recycled fine aggregate (RFA) of 0.15-4.75 mm, and recycled powder (RP) smaller than 0.15 mm) produced from concrete waste on the fresh and hardened mechanical properties of concrete were evaluated. The replacement ratios of natural coarse and fine aggregates by RCA and RFA were 30, 60, and 100%, and those of ordinary Portland cement for RP were 10, 20, and 30%. The results showed that the concrete properties deteriorated with increasing replacement ratio regardless of the type of recycled materials. The properties were reduced in the order of the use of RFA, RCA, and the simultaneous use of RCA and RFA. In addition, concrete with 30% RP showed lower mechanical strength than concrete with 100% RCA and 100% RFA. However, all concretes could be applicable for structural purposes under different environmental exposure conditions. In particular, concretes with 10% RP and 20% RP showed better cost-benefits compared to natural aggregate concrete with 100% ordinary Portland cement. These promising findings provide valuable initiatives for the effective and complete recycling of C&D waste.
Epigenetic mechanisms, namely DNA and histone modifications, are critical regulators of immunity and inflammation which have emerged as potential targets for immunomodulating therapies. The ...prevalence and significant morbidity of periodontitis, in combination with accumulating evidence that genetic, environmental and lifestyle factors cannot fully explain the susceptibility of individuals to disease development, have driven interest in epigenetic regulation as an important factor in periodontitis pathogenesis. Aberrant promoter methylation profiles of genes involved in inflammatory activation, including TLR2, PTGS2, IFNG, IL6, IL8, and TNF, have been observed in the gingival tissue, peripheral blood or buccal mucosa from patients with periodontitis, correlating with changes in expression and disease severity. The expression of enzymes that regulate histone acetylation, in particular histone deacetylases (HDACs), is also dysregulated in periodontitis-affected gingival tissue. Infection of gingival epithelial cells, gingival fibroblasts and periodontal ligament cells with the oral pathogens Porphyromonas gingivalis or Treponema denticola induces alterations in expression and activity of chromatin-modifying enzymes, as well as site-specific and global changes in DNA methylation profiles and in histone acetylation and methylation marks. These epigenetic changes are associated with excessive production of inflammatory cytokines, chemokines, and matrix-degrading enzymes that can be suppressed by small molecule inhibitors of HDACs (HDACi) or DNA methyltransferases. HDACi and inhibitors of bromodomain-containing BET proteins ameliorate inflammation, osteoclastogenesis, and alveolar bone resorption in animal models of periodontitis, suggesting their clinical potential as host modulation therapeutic agents. However, broader application of epigenomic methods will be required to create a comprehensive map of epigenetic changes in periodontitis. The integration of functional studies with global analyses of the epigenetic landscape will provide critical information on the therapeutic and diagnostic potential of epigenetics in periodontal disease.
Histone deacetylase inhibitors (HDACi) display potent therapeutic efficacy in animal models of arthritis and suppress inflammatory cytokine production in rheumatoid arthritis (RA) synovial ...macrophages and tissue.
To determine the molecular mechanisms contributing to the suppressive effects of HDACi on RA synovial cell activation, using interleukin 6 (IL-6) regulation as a model.
RA fibroblast-like synoviocytes (FLS) and healthy donor macrophages were treated with IL-1β, tumour necrosis factor (TNF)α, lipopolysaccharide or polyinosinic:polycytidylic acid (poly(I:C)) in the absence or presence of the HDACi trichostatin A (TSA) or ITF2357 (givinostat). IL-6 production and mRNA expression was measured by ELISA and quantitative PCR (qPCR), respectively. Protein acetylation and the activation of intracellular signalling pathways were assessed by immunoblotting. The DNA-binding activity of nuclear factor κB (NFκB) and activator protein 1 (AP-1) components was measured by ELISA-based assays.
HDACi (0.25-1.0 μM) suppressed RA FLS IL-6 production induced by IL-1β, TNFα and Toll-like receptor ligands. Phosphorylation of mitogen-activated protein kinases and inhibitor of κBα (IκBα) following IL-1β stimulation were unaffected by HDACi, as were AP-1 composition and binding activity, and c-Jun induction. TSA induced a significant reduction in nuclear retention of NFκB in FLS 24 h after IL-1β stimulation, but this did not reduce NFκB transcriptional activity or correlate temporally with reductions in IL-6 mRNA accumulation. HDACi significantly reduced the stability of IL-6 mRNA in FLS and macrophages.
Our study identifies a novel, shared molecular mechanism by which HDACi can disrupt inflammatory cytokine production in RA synovial cells, namely the promotion of mRNA decay, and suggests that targeting HDAC activity may be clinically useful in suppressing inflammation in RA.
To investigate the effects of BET bromodomain protein inhibition on inflammatory activation and functional properties of rheumatoid arthritis synovial fibroblasts (RASF).
The expression of the BET ...bromodomain proteins BRD2, BRD3 and BRD4 was analysed in synovial tissue by immunohistochemistry. RASF were stimulated with tumour necrosis factor (TNF)-α, interleukin (IL)-1β and toll-like receptor (TLR) ligands (Pam3, pIC and lipopolysaccharide (LPS)) in the presence or absence of the BET inhibitor I-BET151, or siRNA targeting BRD2, BRD3 and BRD4. RASF expression of inflammatory mediators, including MMP1, MMP3, IL-6 and IL-8, was measured by q-PCR, q-PCR array and ELISA. Cellular viability, apoptosis, proliferation and chemoattractive properties of RASF were investigated using MTT, cell apoptosis ELISA, BrdU-based proliferation and transwell migration assays.
BRD2, BRD3 and BRD4 proteins were detected in rheumatoid arthritis (RA) synovial tissue, expressed in both RASF and macrophages. I-BET151 suppressed cytokine and TLR ligand-induced secretion of MMP1, MMP3, IL-6 and IL-8, and mRNA expression of more than 70% of genes induced by TNF-α and IL-1β. Combined silencing of BRD2, BRD3 and BRD4 significantly reduced cytokine and TLR ligand-induced expression of a subset of gene products targeted by I-BET151, including MMP1, CXCL10 and CXCL11. I-BET151 treatment of RASF reduced RASF proliferation, and the chemotactic potential for peripheral blood leucocytes of RASF conditioned medium.
Inhibition of BET family proteins suppresses the inflammatory, matrix-degrading, proliferative and chemoattractive properties of RASF and suggests a therapeutic potential in the targeting of epigenetic reader proteins in RA.
Much of the biology surrounding macrophage functional specificity has arisen through examining inflammation-induced polarizing signals, but this also occurs in homeostasis, requiring tissue-specific ...environmental triggers that influence macrophage phenotype and function. The TAM receptor family of receptor tyrosine kinases (Tyro3, Axl and MerTK) mediates the non-inflammatory removal of apoptotic cells by phagocytes through the bridging phosphatidylserine-binding molecules growth arrest-specific 6 (Gas6) or Protein S. We show that one such TAM receptor (Axl) is exclusively expressed on mouse airway macrophages, but not interstitial macrophages and other lung leukocytes, under homeostatic conditions and is constitutively ligated to Gas6. Axl expression is potently induced by granulocyte-macrophage colony-stimulating factor expressed in the healthy and inflamed airway, and by type I interferon or Toll-like receptor-3 stimulation on human and mouse macrophages, indicating potential involvement of Axl in apoptotic cell removal under inflammatory conditions. Indeed, an absence of Axl does not cause sterile inflammation in health, but leads to exaggerated lung inflammatory disease upon influenza infection. These data imply that Axl allows specific identification of airway macrophages, and that its expression is critical for macrophage functional compartmentalization in the airspaces or lung interstitium. We propose that this may be a critical feature to prevent excessive inflammation because of secondary necrosis of apoptotic cells that have not been cleared by efferocytosis.
The decrease in the quality of recycled aggregate due to an increase in the number of recycling is a primary factor that limits the multi-recycling of concrete. This degradation adversely affects ...concrete performance; thus, the characteristics of recycled aggregate should be considered during the mix design stage, but little research has taken that into account. This study investigates the effect of the equivalent mortar volume (EMV) mix design on some physical, mechanical and durability properties of concrete made of multiple recycled coarse aggregates at 50% and 100% replacement ratios compared to concrete made by the conventional mix design (CMD). The results showed that the performances of concrete by the CMD decreased with an increasing number of recycling cycles. The properties of EMV-based concrete deteriorated with an increase in the number of recycling cycles at 100% replacement ratio due to poor workability caused by a shortage of fresh mortar. However, at 50% replacement, the EMV-based concrete exhibited similar performance across the three cycles of recycling, as well as improved properties over natural aggregate concrete. This study demonstrated that an appropriate mix design and optimal aggregate replacement ratio can offset the property loss of multiple recycled aggregate concrete.
Macrophages contribute significantly to the pathology of many chronic inflammatory diseases, including rheumatoid arthritis (RA), asthma, and chronic obstructive pulmonary disease. Macrophage ...activation and survival are tightly regulated by reversible acetylation and deacetylation of histones, transcription factors, and structural proteins. Although histone deacetylase (HDAC) inhibitors (HDACis) demonstrate therapeutic effects in animal models of chronic inflammatory disease, depressed macrophage HDAC activity in patients with asthma, chronic obstructive pulmonary disease, or RA may contribute to inflammation in these diseases, potentially contraindicating the therapeutic administration of HDACis. In this study, we directly examined whether HDACis could influence the activation of macrophages derived from the inflamed joints of patients with RA. We found that inhibition of class I/II HDACs or class III sirtuin HDACs potently blocked the production of IL-6 and TNF-alpha by macrophages from healthy donors and patients with RA. Two HDACis, trichostatin A and nicotinamide, selectively induced macrophage apoptosis associated with specific downregulation of the antiapoptotic protein Bfl-1/A1, and inflammatory stimuli enhanced the sensitivity of macrophages to HDACi-induced apoptosis. Importantly, inflammatory and angiogenic cytokine production in intact RA synovial biopsy explants was also suppressed by HDACis. Our study identifies redundant, but essential, roles for class I/II and sirtuin HDACs in promoting inflammation, angiogenesis, and cell survival in RA.
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