Synthetic glucocorticoids (GCs), one of the most effective treatments for chronic inflammatory and autoimmune conditions in children, have adverse effects on the growing skeleton. GCs inhibit ...angiogenesis in growing bone, but the underlying mechanisms remain unclear. Here, we show that GC treatment in young mice induces vascular endothelial cell senescence in metaphysis of long bone, and that inhibition of endothelial cell senescence improves GC-impaired bone angiogenesis with coupled osteogenesis. We identify angiogenin (ANG), a ribonuclease with pro-angiogenic activity, secreted by osteoclasts as a key factor for protecting the neighboring vascular cells against senescence. ANG maintains the proliferative activity of endothelial cells through plexin-B2 (PLXNB2)-mediated transcription of ribosomal RNA (rRNA). GC treatment inhibits ANG production by suppressing osteoclast formation in metaphysis, resulting in impaired endothelial cell rRNA transcription and subsequent cellular senescence. These findings reveal the role of metaphyseal blood vessel senescence in mediating the action of GCs on growing skeleton and establish the ANG/PLXNB2 axis as a molecular basis for the osteoclast-vascular interplay in skeletal angiogenesis.
Macrophage polarization and allergic asthma Saradna, Arjun; Do, Danh C.; Kumar, Shruthi ...
Translational research : the journal of laboratory and clinical medicine,
01/2018, Letnik:
191
Journal Article
Recenzirano
Odprti dostop
Allergic asthma is associated with airway inflammation and airway hyperresponsiveness. Macrophage polarization has been shown to have a profound impact on asthma pathogenesis. On exposure to local ...microenvironments, recruited macrophages can be polarized into either classically activated (or M1) or alternatively activated (or M2) phenotypes. Macrophage polarization has been heavily associated with development of asthma. The process of regulation of macrophage polarization involves an intricate interplay between various cytokines, chemokines, transcriptional factors, and immune-regulatory cells. Different signals from the microenvironment are controlled by different receptors on the macrophages to initiate various macrophage polarization pathways. Most importantly, there is an increased attention on the epigenetic changes (eg, microRNAs, DNA methylation, and histone modification) that impact macrophage functional responses and M1/M2 polarization through modulating cellular signaling and signature gene expression. Thus, modulation of macrophage phenotypes through molecular intervention by targeting some of those potential macrophage regulators may have therapeutic potential in the treatment of allergic asthma and other allergic diseases. In this review, we will discuss the origin of macrophages, characterization of macrophages, macrophage polarization in asthma, and the underlying mechanisms regarding allergen-induced macrophage polarization with emphasis on the regulation of epigenetics, which will provide new insights into the therapeutic strategy for asthma.
Autophagy plays an important role in causing inflammatory responses initiated by environmental pollutants and respiratory tract infection.
We sought to investigate the role of cockroach ...allergen–induced excessive activation of autophagy in allergic airway inflammation and its underlying molecular mechanisms.
Environmental allergen–induced autophagy was investigated in the primary human bronchial epithelial cells (HBECs) and lung tissues of asthmatic mouse model and patients. The role of autophagy in asthma development was examined by using autophagy inhibitor 3-methyladenine in an asthma mouse model. Furthermore, the involvements of reactive oxygen species (ROS) and oxidized Ca2+/calmodulin-dependent protein kinase II (ox-CaMKII) signaling in regulating autophagy during asthma were examined in allergen-treated HBECs and mouse model.
Cockroach allergen activated autophagy in HBECs and in the lung tissues from asthmatic patients and mice. Autophagy inhibitor 3-methyladenine significantly attenuated airway hyperresponsiveness, TH2-associated lung inflammation, and ROS generation. Mechanistically, we demonstrated a pathological feedforward circuit between cockroach allergen–induced ROS and autophagy that is mediated through CaMKII oxidation. Furthermore, transgenic mice with ROS-resistant CaMKII MM-VVδ showed attenuation of TH2-associated lung inflammation and autophagy. Mitochondrial ox-CaMKII inhibition induced by adenovirus carrying mitochondrial-targeted inhibitor peptide CaMKIIN suppresses cockroach allergen–induced autophagy, mitochondrial dysfunction, mitophagy, and cytokine production in HBECs. Finally, mitochondrial CaMKII inhibition suppressed the expression of one of the key ubiquitin-binding autophagy receptors, optineurin, and its recruitment to fragmented mitochondria. Optineurin knockdown inhibited cockroach allergy–induced mitophagy.
Our data suggest a previously uncovered axis of allergen-ROS-ox-CaMKII-mitophagy in the development of allergic airway inflammation and asthma.
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Environmental pollutants and allergens induce oxidative stress and mitochondrial dysfunction, leading to key features of allergic asthma. Dysregulations in autophagy, mitophagy, and cellular ...senescence have been associated with environmental pollutant and allergen-induced oxidative stress, mitochondrial dysfunction, secretion of multiple inflammatory proteins, and subsequently development of asthma. Particularly, particulate matter 2.5 (PM
) has been reported to induce autophagy in the bronchial epithelial cells through activation of AMP-activated protein kinase (AMPK), drive mitophagy through activating PTEN-induced kinase 1(PINK1)/Parkin pathway, and induce cell cycle arrest and senescence. Intriguingly, allergens, including
(OVA),
, and
, have also been shown to induce autophagy through activation of different signaling pathways. Additionally, mitochondrial dysfunction can induce cell senescence due to excessive ROS production, which affects airway diseases. Although autophagy and senescence share similar properties, recent studies suggest that autophagy can either accelerate the development of senescence or prevent senescence. Thus, in this review, we evaluated the literature regarding the basic cellular processes, including autophagy, mitophagy, and cellular senescence, explored their molecular mechanisms in the regulation of the initiation and downstream signaling. Especially, we highlighted their involvement in environmental pollutant/allergen-induced major phenotypic changes of asthma such as airway inflammation and remodeling and reviewed novel and critical research areas for future studies. Ultimately, understanding the regulatory mechanisms of autophagy, mitophagy, and cellular senescence may allow for the development of new therapeutic targets for asthma.
Renal interstitial fibrosis is the pathological basis of end-stage renal disease, in which the heterogeneity of macrophages in renal microenvironment plays an important role. However, the molecular ...mechanisms of macrophage plasticity during renal fibrosis progression remain unclear. In this study, we found for the first time that increased expression of Twist1 in macrophages was significantly associated with the severity of renal fibrosis in IgA nephropathy patients and mice with unilateral ureteral obstruction (UUO). Ablation of Twist1 in macrophages markedly alleviated renal tubular injury and renal fibrosis in UUO mice, accompanied by a lower extent of macrophage infiltration and M2 polarization in the kidney. The knockdown of Twist1 inhibited the chemotaxis and migration of macrophages, at least partially, through the CCL2/CCR2 axis. Twist1 downregulation inhibited M2 macrophage polarization and reduced the secretion of the profibrotic factors Arg-1, MR (CD206), IL-10, and TGF-β. Galectin-3 was decreased in the macrophages of the conditional Twist1-deficient mice, and Twist1 was shown to directly activate galectin-3 transcription. Up-regulation of galectin-3 recovered Twist1-mediated M2 macrophage polarization. In conclusion, Twist1/galectin-3 signaling regulates macrophage plasticity (M2 phenotype) and promotes renal fibrosis. This study could suggest new strategies for delaying kidney fibrosis in patients with chronic kidney disease.
Background Atopic dermatitis (AD) is a chronic inflammatory skin disease that is characterized by a defective skin barrier function. Recent studies have reported mutations of the skin barrier gene ...encoding filaggrin in a subset of patients with AD. Objective We investigated whether reduced filaggrin expression was found in patients with AD who were not carriers of known filaggrin mutations and whether filaggrin expression was modulated by the atopic inflammatory response. Methods Filaggrin expression was measured in skin biopsies and cultured keratinocytes using real-time RT-PCR and immunohistochemistry. Filaggrin loss-of-function mutations were screened in a total of 69 subjects. Results Compared with normal skin, filaggrin expression was significantly reduced ( P < .05) in acute AD skin, with further reduction seen in acute lesions from 3 European American subjects with AD who were heterozygous for the 2282del4 mutation. This was confirmed by using immunohistochemistry. AD skin is characterized by the overexpression of IL-4 and IL-13. Keratinocytes differentiated in the presence of IL-4 and IL-13 exhibited significantly reduced filaggrin gene expression (0.04 ± 0.01 ng filaggrin/ng glyceraldehyde 3-phosphate dehydrogenase; P < .05) compared with media alone (0.16 ± 0.03). Conclusion Patients with AD have an acquired defect in filaggrin expression that can be modulated by the atopic inflammatory response. Clinical implications The atopic immune response contributes to the skin barrier defect in AD; therefore, neutralization of IL-4 and IL-13 could improve skin barrier integrity.
Aging is a significant risk factor for various diseases, including asthma, and it often leads to poorer clinical outcomes, particularly in elderly individuals. It is recognized that age-related ...diseases are due to a time-dependent accumulation of cellular damage, resulting in a progressive decline in cellular and physiological functions and an increased susceptibility to chronic diseases. The effects of aging affect not only the elderly but also those of younger ages, posing significant challenges to global healthcare. Thus, understanding the molecular mechanisms associated with aging in different diseases is essential. One intriguing factor is the aryl hydrocarbon receptor (AhR), which serves as a cytoplasmic receptor and ligand-activated transcription factor and has been linked to the aging process. Here, we review the literature on several major hallmarks of aging, including mitochondrial dysfunction, cellular senescence, autophagy, mitophagy, epigenetic alterations, and microbiome disturbances. Moreover, we provide an overview of the impact of AhR on these hallmarks by mediating responses to environmental exposures, particularly in relation to the immune system. Furthermore, we explore how aging hallmarks affect clinical characteristics, inflammatory features, exacerbations, and the treatment of asthma. It is suggested that AhR signaling may potentially play a role in regulating asthma phenotypes in elderly populations as part of the aging process.
Background Atopic dermatitis (AD) is a chronic inflammatory skin disease that is characterized by a defective skin barrier function. Recent studies have reported mutations of the skin barrier gene ...encoding filaggrin in a subset of patients with AD. Objective We investigated whether reduced filaggrin expression was found in patients with AD who were not carriers of known filaggrin mutations and whether filaggrin expression was modulated by the atopic inflammatory response. Methods Filaggrin expression was measured in skin biopsies and cultured keratinocytes using real-time RT-PCR and immunohistochemistry. Filaggrin loss-of-function mutations were screened in a total of 69 subjects. Results Compared with normal skin, filaggrin expression was significantly reduced ( P < .05) in acute AD skin, with further reduction seen in acute lesions from 3 European American subjects with AD who were heterozygous for the 2282del4 mutation. This was confirmed by using immunohistochemistry. AD skin is characterized by the overexpression of IL-4 and IL-13. Keratinocytes differentiated in the presence of IL-4 and IL-13 exhibited significantly reduced filaggrin gene expression (0.04 ± 0.01 ng filaggrin/ng glyceraldehyde 3-phosphate dehydrogenase; P < .05) compared with media alone (0.16 ± 0.03). Conclusion Patients with AD have an acquired defect in filaggrin expression that can be modulated by the atopic inflammatory response. Clinical implications The atopic immune response contributes to the skin barrier defect in AD; therefore, neutralization of IL-4 and IL-13 could improve skin barrier integrity.
Mesenchymal stem/progenitor cells (MSPCs) undergo rapid self-renewal and differentiation, contributing to fast skeletal growth during childhood and puberty. It remains unclear whether these cells ...change their properties during late puberty to young adulthood, when bone growth and accrual decelerate. Here we show that MSPCs in primary spongiosa of long bone in mice at late puberty undergo normal programmed senescence, characterized by loss of nestin expression. MSPC senescence is epigenetically controlled by the polycomb histone methyltransferase enhancer of zeste homolog 2 (Ezh2) and its trimethylation of histone H3 on Lysine 27 (H3K27me3) mark. Ezh2 maintains the repression of key cell senescence inducer genes through H3K27me3, and deletion of Ezh2 in early pubertal mice results in premature cellular senescence, depleted MSPCs pool, and impaired osteogenesis as well as osteoporosis in later life. Our data reveals a programmed cell fate change in postnatal skeleton and unravels a regulatory mechanism underlying this phenomenon.
Antagonistic pleiotropy is a foundational theory that predicts aging-related diseases are the result of evolved genetic traits conferring advantages early in life. Here we examine CaMKII, a ...pluripotent signaling molecule that contributes to common aging-related diseases, and find that its activation by reactive oxygen species (ROS) was acquired more than half-a-billion years ago along the vertebrate stem lineage. Functional experiments using genetically engineered mice and flies reveal ancestral vertebrates were poised to benefit from the union of ROS and CaMKII, which conferred physiological advantage by allowing ROS to increase intracellular Ca
and activate transcriptional programs important for exercise and immunity. Enhanced sensitivity to the adverse effects of ROS in diseases and aging is thus a trade-off for positive traits that facilitated the early and continued evolutionary success of vertebrates.
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