Cells In Inflammatory Disease Research Articles

Autophagy-mediated NKG2D internalization impairs NK cell function and exacerbates radiation pneumonitis.

Radiation pneumonitis is a critical complication that constrains the use of radiation therapy for thoracic malignancies, leading to substantial morbidity via respiratory distress and lung function impairment. The role of Natural killer (NK) cells in inflammatory diseases is well-documented; however, their involvement in radiation pneumonitis is not fully understood. To explore the involvement of NK cells in radiation pneumonitis, we analyzed tissue samples for NK cell presence and function. The study utilized immunofluorescence staining, western blotting, and immunoprecipitation to investigate CXCL10 and ROS levels, autophagy activity, and NKG2D receptor dynamics in NK cells derived from patients and animal models subjected to radiation. In this study, we observed an augmented infiltration of NK cells in tissues affected by radiation pneumonitis, although their function was markedly diminished. In animal models, enhancing NK cell activity appeared to decelerate the disease progression. Concomitant with the disease course, there was a notable upsurge in CXCL10 and ROS levels. CXCL10 was found to facilitate NK cell migration through CXCR3 receptor activation. Furthermore, evidence of excessive autophagy in patient NK cells was linked to ROS accumulation, as indicated by immunofluorescence and Western blot analyses. The association between the NKG2D receptor and its adaptor proteins (AP2 subunits AP2A1 and AP2M1), LC3, and lysosomes was intensified after radiation exposure, as demonstrated by immunoprecipitation. This interaction led to NKG2D receptor endocytosis and subsequent lysosomal degradation. Our findings delineate a mechanism by which radiation-induced lung injury may suppress NK cell function through an autophagy-dependent pathway. The dysregulation observed suggests potential therapeutic targets; hence, modulating autophagy and enhancing NK cell activity could represent novel strategies for mitigating radiation pneumonitis.

Human intestinal B cells in inflammatory diseases.

The intestinal lumen contains an abundance of bacteria, viruses and fungi alongside ingested material that shape the chronically active intestinal immune system from early life to maintain the integrity of the gut epithelial barrier. In health, the response is intricately balanced to provide active protection against pathogen invasion whilst tolerating food and avoiding inflammation. B cells are central to achieving this protection. Their activation and maturation generates the body's largest plasma cell population that secretes IgA, and the niches they provide support systemic immune cell specialization. For example, the gut supports the development and maturation of a splenic Bcell subset - the marginal zone B cells. In addition, cells such as the Tfollicular helper cells, which are enriched in many autoinflammatory diseases, are intrinsically associated with the germinal centre microenvironment that is more abundant in the gut than in any other tissue in health. In this Review, we discuss intestinal B cells and their role when a loss of homeostasis results in intestinal and systemic inflammatory diseases.

DOT1L regulates lipid biosynthesis and inflammatory responses in macrophages and promotes atherosclerotic plaque stability.

Macrophages are critical immune cells in inflammatory diseases, and their differentiation and function are tightly regulated by histone modifications. H3K79 methylation is a histone modification associated with active gene expression, and DOT1L is the only histone methyltransferase for H3K79. Here we determine the role of DOT1L in macrophages by applying a selective DOT1L inhibitor in mouse and human macrophages and using myeloid-specific Dot1l-deficient mice. We found that DOT1L directly regulates macrophage function by controlling lipid biosynthesis gene programs including central lipid regulators like sterol regulatory element-binding proteins SREBP1 and SREBP2. DOT1L inhibition also leads to macrophage hyperactivation, which is associated with disrupted SREBP pathways. Invivo, myeloid Dot1l deficiency reduces atherosclerotic plaque stability and increases the activation of inflammatory plaque macrophages. Our data show that DOT1L is a crucial regulator of macrophage inflammatory responses and lipid regulatory pathways and suggest a high relevance of H3K79 methylation in inflammatory disease.

The Role of Exosomes in Inflammatory Diseases and Tumor-Related Inflammation

Inflammation plays a decisive role in inducing tumorigenesis, promoting tumor development, tumor invasion and migration. The interaction of cancer cells with their surrounding stromal cells and inflammatory cells further forms an inflammatory tumor microenvironment (TME). The large number of cells present within the TME, such as mesenchymal stem cells (MSCs), macrophages, neutrophils, etc., play different roles in the changing TME. Exosomes, extracellular vesicles released by various types of cells, participate in a variety of inflammatory diseases and tumor-related inflammation. As an important communication medium between cells, exosomes continuously regulate the inflammatory microenvironment. In this review, we focused on the role of exosomes in inflammatory diseases and tumor-related inflammation. In addition, we also summarized the functions of exosomes released by various cells in inflammatory diseases and in the TME during the transformation of inflammatory diseases to tumors. We discussed in depth the potential of exosomes as targets and tools to treat inflammatory diseases and tumor-related inflammation.

Biologically Synthesized Peptides Show Remarkable Inhibition Activity against Angiotensin-Converting Enzyme: A Promising Approach for Peptide Development against Autoimmune Diseases.

Angiotensin-converting enzyme (ACE) regulates several biological functions besides its vital role in immune functions. ACE is elevated in immune cells in inflammatory diseases including atherosclerosis, granuloma, chronic kidney disease, and also autoimmune diseases, like multiple sclerosis, rheumatoid arthritis, and type I diabetes. No significant information prevails in the literature regarding the isolation, identification, and profiling of potential ACE inhibitory peptides. In the present study, indigenous crop varieties like seeds (peanut, corn, oat, sunflower, chickpea, parsley, cottonseed, papaya, sesame, and flaxseed) were used to evaluate their ACE inhibition activity. Variables including hydrolysis time, enzyme-to-substrate ratio (E/S), pH, and temperature were standardized to acquire the most suitable and optimum ACE inhibition activity. Seeds of cotton, chickpea, and peanuts displayed remarkably maximum ACE inhibition activity than other plants. The study disclosed that maximum ACE inhibitory activity (86%) was evaluated from cottonseed at pH 8.0, temperature of 45°C, hydrolysis time of 2 hrs, and enzyme to the substrate (E/S) ratio of 1 : 5 followed by peanuts (76%) and chickpea (55%). SDS-PAGE confirmed that vicilin protein is present in cottonseed and peanut seed while cruciferin and napin proteins are present in chickpeas. LC-MS/MS analysis disclosed potential novel peptides in hydrolyzed cottonseed that can be ascribed as potential ACE inhibitors which have never been reported and studied earlier. The current study further showed that cottonseed peptides due to their promising ACE inhibitory activity can be a valuable source in the field of ACE inhibitor development.

Opportunities to target mast cells in inflammatory diseases expand

Drugs that target mast cells could provide novel options to treat disorders involving chronic allergic inflammation. Drugs that target mast cells could provide novel options to treat disorders involving chronic allergic inflammation.

CD4+ T cells in inflammatory diseases: pathogenic T-helper cells and the CD69-Myl9 system.

CD4+ T cells not only direct immune responses against infectious micro-organisms but are also involved in the pathogenesis of inflammatory diseases. In the last two to three decades, various researchers have identified and characterized several functional CD4+ T-cell subsets, including T-helper 1 (Th1), Th2, Th9 and Th17 cells and regulatory T (Treg) cells. In this mini-review, we introduce the concept of pathogenic Th cells that induce inflammatory diseases with a model of disease induction by a population of pathogenic Th cells: the 'pathogenic Th population disease-induction model'. We will focus on Th2 cells that induce allergic airway inflammation-pathogenic Th2 cells (Tpath2 cells)-and discuss the nature of Tpath2 cells that shape the pathology of chronic inflammatory diseases. Various Tpath2-cell subsets have been identified and their unique features are summarized in mouse and human systems. Second, we will discuss how Th cells migrate and are maintained in chronic inflammatory lesions. We propose a model known as the 'CD69-Myl9 system'. CD69 is a cell surface molecule expressed on activated T cells and interaction with its ligand myosin light chain 9 (Myl9) is required for the induction of inflammatory diseases. Myl9 molecules in the small vessels of inflamed lungs may play a crucial role in the migration of activated T cells into inflammatory lesions. Emerging evidence may provide new insight into the pathogenesis of chronic inflammatory diseases and contribute to the development of new therapeutic strategies for intractable inflammatory disorders.

The Effect and Regulatory Mechanism of High Mobility Group Box-1 Protein on Immune Cells in Inflammatory Diseases.

High mobility group box-1 protein (HMGB1), a member of the high mobility group protein superfamily, is an abundant and ubiquitously expressed nuclear protein. Intracellular HMGB1 is released by immune and necrotic cells and secreted HMGB1 activates a range of immune cells, contributing to the excessive release of inflammatory cytokines and promoting processes such as cell migration and adhesion. Moreover, HMGB1 is a typical damage-associated molecular pattern molecule that participates in various inflammatory and immune responses. In these ways, it plays a critical role in the pathophysiology of inflammatory diseases. Herein, we review the effects of HMGB1 on various immune cell types and describe the molecular mechanisms by which it contributes to the development of inflammatory disorders. Finally, we address the therapeutic potential of targeting HMGB1.

Strategies to Potentiate Paracrine Therapeutic Efficacy of Mesenchymal Stem Cells in Inflammatory Diseases.

Mesenchymal stem cells (MSCs) have been developed as cell therapeutics for various immune disorders using their immunoregulatory properties mainly exerted by their paracrine functions. However, variation among cells from different donors, as well as rapid clearance after transplantation have impaired the uniform efficacy of MSCs and limited their application. Recently, several strategies to overcome this limitation have been suggested and proven in pre-clinical settings. Therefore, in this review article, we will update the knowledge on bioengineering strategies to improve the immunomodulatory functions of MSCs, including genetic modification and physical engineering.

Infiltration of Mast Cells in Scalp Biopsies of Patients with Alopcia Areata or Androgenic Alopecia Versus Healthy Individuals: A Case Control Study.

Background: Alopecia areata (AA) and androgenic alopecia (AGA) are of the most common types of alopecias. Recently, the role of mastcells in inflammatory diseases has become the focus of many studies. However, few studies have been conducted on their role in AA and AGA. Therefore, our study aimed to quantitatively evaluate the presence of mastcells in the AA and AGA specimens. Materials and Methods: Three groups of AA, AGA, and healthy control were studied (each group with 20 subjects). Patients were randomly selected from those referred to the dermatology clinics of Shahid Beheshti University. Specimens were obtained from the scalp, and perifollicular and perivascular areas were investigated. Results: Significantly higher perifollicular and perivascular mastcell counts were seen in both AGA and AA groups as compared to healthy control (P<0.001 for both). Moreover, AA patients had more frequent perivascular mastcells than the AGA group (P=0.042). Among patients aged <40 years, perifollicular and perivascular mastcell counts were not significantly different among three groups; however, subjects over 40 years of age in both groups had significantly more perifollicular and perivascular mastcells than healthy participants. There was a significant positive correlation between disease severity and mast cell counts in both perifollicular and perivascular areas in AA patients (P=0.001 for both). Conclusion: There is a significantly increased infiltration of mastcells in AA and AGA patients, and this increase is age and severity dependent. Moreover, the increase in mastcell proliferation is more dominant in AA patients.

Infiltration of Mast Cells in Scalp Biopsies of Patients with Alopecia Areata or Androgenic Alopecia Versus Healthy Individuals: A Case-Control Study

Background: Alopecia areata (AA) and androgenic alopecia (AGA) are the most common types of alopecias. Recently, the role of mast cells in inflammatory diseases has become the focus of many studies. However, few studies have been conducted on their role in AA and AGA. Therefore, our study aimed to quantitatively evaluate the presence of mast cells in the AA and AGA specimens.Materials and Methods: Three groups of AA, AGA, and healthy control were studied (each group with 20 subjects). Patients were randomly selected from those referred to the dermatology clinics of Shahid Beheshti University. Specimens were obtained from the scalp, and perifollicular and perivascular areas were investigated. Results: Significantly higher perifollicular and perivascular mast cell counts were seen in both AGA and AA groups compared to healthy control (P&lt;0.001 for both). Moreover, AA patients had more frequent perivascular mast cells than the AGA group (P=0.042). Among patients aged &lt;40 years, perifollicular and perivascular mast cell counts were not significantly different among the three groups; however, subjects over 40 years of age in both groups had significantly more perifollicular and perivascular mast cells than healthy participants. There was a significant positive correlation between disease severity and mast cell counts in both perifollicular and perivascular areas in AA patients (P=0.001 for both). Conclusion: There was a significantly increased infiltration of mast cells in AA and AGA patients, and this increase was age and severity dependent. Moreover, the increase in mast cell proliferation is more dominant in AA patients. [GMJ.2020;9:e1962]

Protective roles for myeloid cells in neuroinflammation.

Myeloid cells represent the major cellular component of innate immune responses. Myeloid cells include monocytes and macrophages, granulocytes (neutrophils, basophils and eosinophils) and dendritic cells (DC). The role of myeloid cells has been broadly described both in physiological and in pathological conditions. All tissues or organs are equipped with resident myeloid cells, such as parenchymal microglia in the brain, which contribute to maintaining homeostasis. Moreover, in case of infection or tissue damage, other myeloid cells such as monocytes or granulocytes (especially neutrophils) can be recruited from the circulation, at first to promote inflammation and later to participate in repair and regeneration. This review aims to address the regulatory roles of myeloid cells in inflammatory diseases of the central nervous system (CNS), with a particular focus on recent work showing induction of suppressive function via stimulation of innate signalling in multiple sclerosis (MS) and its animal model experimental autoimmune encephalomyelitis (EAE).

Microbiota-Propelled T Helper 17 Cells in Inflammatory Diseases and Cancer.

Technologies allowing genetic sequencing of the human microbiome are opening new realms to discovery. The host microbiota substantially impacts immune responses both in immune-mediated inflammatory diseases (IMIDs) and in tumors affecting tissues beyond skin and mucosae. However, a mechanistic link between host microbiota and cancer or IMIDs has not been well established. Here, we propose T helper 17 (TH17) lymphocytes as the connecting factor between host microbiota and rheumatoid or psoriatic arthritides, multiple sclerosis, breast or ovarian cancer, and multiple myeloma. We theorize that similar mechanisms favor the expansion of gut-borne TH17 cells and their deployment at the site of inflammation in extraborder IMIDs and tumors, where TH17 cells are driving forces. Thus, from a pathogenic standpoint, tumors may share mechanistic routes with IMIDs. A review of similarities and divergences in microbiota-TH17 cell interactions in IMIDs and cancer sheds light on previously ignored pathways in either one of the two groups of pathologies and identifies novel therapeutic avenues.

MRI coupled with clinically-applicable iron oxide nanoparticles reveals choroid plexus involvement in a murine model of neuroinflammation

Choroid plexus (ChPs) are involved in the early inflammatory response that occurs in many brain disorders. However, the activation of immune cells within the ChPs in response to neuroinflammation is still largely unexplored in-vivo. There is therefore a crucial need for developing imaging tool that would allow the non-invasive monitoring of ChP involvement in these diseases. Magnetic resonance imaging (MRI) coupled with superparamagnetic particles of iron oxide (SPIO) is a minimally invasive technique allowing to track phagocytic cells in inflammatory diseases. Our aim was to investigate the potential of ultrasmall SPIO (USPIO)-enhanced MRI to monitor ChP involvement in-vivo in a mouse model of neuroinflammation obtained by intraperitoneal administration of lipopolysaccharide. Using high resolution MRI, we identified marked USPIO-related signal drops in the ChPs of animals with neuroinflammation compared to controls. We confirmed these results quantitatively using a 4-points grading system. Ex-vivo analysis confirmed USPIO accumulation within the ChP stroma and their uptake by immune cells. We validated the translational potential of our approach using the clinically-applicable USPIO Ferumoxytol. MR imaging of USPIO accumulation within the ChPs may serve as an imaging biomarker to study ChP involvement in neuroinflammatory disorders that could be applied in a straightforward way in clinical practice.

C1q and TNF related protein 1 regulates expression of inflammatory genes in vascular smooth muscle cells

C1q and TNF related protein 1 (C1QTNF1) is known to be associated with coronary artery diseases. However, the molecular function of C1QTNF1 on the vascular smooth muscles remains to be investigated. This study was therefore undertaken to investigate the effect of C1QTNF1 on gene expression of human smooth muscle cells and to reveal potential molecular mechanisms mediated by C1QTNF1. Vascular smooth muscle cells were incubated with recombinant C1QTNF1 for 16h, followed by determining any change in mRNA expressions by Affymetrix genechip. Gene ontology (GO), KEGG pathway, and protein-protein interaction (PPI) network were analyzed in differentially expressed genes. In addition, validation of microarray data was performed using quantitative real-time PCR. The mRNA expressions of annotated 74 genes were significantly altered after incubation with recombinant C1QTNF1; 41 genes were up-regulated and 33 down-regulated. The differentially expressed genes were enriched in biological processes and KEGG pathways associated with inflammatory responses. In the PPI network analysis, IL-6, CCL2, and ICAM1 were identified as potential key genes with relatively high degree. The cluster analysis in the PPI network identified a significant module composed of upregulated genes, such as IL-6, CCL2, NFKBIA, SOD2, and ICAM1. The quantitative real-time PCR results of potential key genes were consistent with microarray data. The results in the present study provide insights on the effects of C1QTNF1 on gene expression of smooth muscle cells. We believe our findings will help to elucidate the molecular mechanisms regarding the functions of C1QTNF1 on smooth muscle cells in inflammatory diseases.

Smiglaside A ameliorates LPS-induced acute lung injury by modulating macrophage polarization via AMPK-PPARγ pathway

Macrophages, which have various phenotypes and diverse functions, are becoming the target cells in inflammatory diseases. In this study, we evaluated the effects of the natural product smiglaside A, a phenylpropanoid glycoside isolated from the traditional Chinese medicinal herb Smilax riparia, on macrophage polarization and investigated the underlying mechanisms. We found that smiglaside A promoted M2 polarization and reduced M1 polarization in LPS-stimulated RAW264.7 cells and primary mouse peritoneal macrophages. Further mechanistic studies showed that the promoting effect of smiglaside A on M2 polarization was attenuated by pharmacological inhibition or gene silencing of AMP-activated protein kinase (AMPK) or peroxisome proliferator-activated receptor γ (PPARγ). Moreover, smiglaside A-enhanced PPARγ activity was prevented by the AMPK inhibitor compound C and by an siRNA. These findings indicate that the AMPK-PPARγ pathway is involved in promotion of M2 macrophages by smiglaside A. In a mouse model of LPS-induced acute lung injury, smiglaside A significantly increased the survival rate of LPS-injected mice and ameliorated the LPS-induced inflammatory response and lung damage. In addition, smiglaside A enhanced the protein expression levels of phosphorylated AMPK and PPARγ in the lung and promoted alveolar macrophages to the M2 phenotype in this mouse model. Taken together, our results indicate that smiglaside A can promote macrophage polarization to an anti-inflammatory M2 phenotype via stimulating the AMPK-PPARγ signaling pathway. Our study may provide novel approaches and/or targets for drug development to treat inflammatory diseases such as acute lung injury and sepsis.

Immunoregulatory mechanisms of mesenchymal stem and stromal cells in inflammatory diseases.

Mesenchymal stem cells (MSCs; also referred to as mesenchymal stromal cells) have attracted much attention for their ability to regulate inflammatory processes. Their therapeutic potential is currently being investigated in various degenerative and inflammatory disorders such as Crohn's disease, graft-versus-host disease, diabetic nephropathy and organ fibrosis. The mechanisms by which MSCs exert their therapeutic effects are multifaceted, but in general, these cells are thought to enable damaged tissues to form a balanced inflammatory and regenerative microenvironment in the presence of vigorous inflammation. Studies over the past few years have demonstrated that when exposed to an inflammatory environment, MSCs can orchestrate local and systemic innate and adaptive immune responses through the release of various mediators, including immunosuppressive molecules, growth factors, exosomes, chemokines, complement components and various metabolites. Interestingly, even nonviable MSCs can exert beneficial effects, with apoptotic MSCs showing immunosuppressive functions in vivo. Because the immunomodulatory capabilities of MSCs are not constitutive but rather are licensed by inflammatory cytokines, the net outcomes of MSC activation might vary depending on the levels and the types of inflammation within the residing tissues. Here, we review current understanding of the immunomodulatory mechanisms of MSCs and the issues related to their therapeutic applications.

Metabolic Adaptations of CD4+ T Cells in Inflammatory Disease.

A controlled and self-limiting inflammatory reaction generally results in removal of the injurious agent and repair of the damaged tissue. However, in chronic inflammation, immune responses become dysregulated and prolonged, leading to tissue destruction. The role of metabolic reprogramming in orchestrating appropriate immune responses has gained increasing attention in recent years. Proliferation and differentiation of the T cell subsets that are needed to address homeostatic imbalance is accompanied by a series of metabolic adaptations, as T cells traveling from nutrient-rich secondary lymphoid tissues to sites of inflammation experience a dramatic shift in microenvironment conditions. How T cells integrate information about the local environment, such as nutrient availability or oxygen levels, and transfer these signals to functional pathways remains to be fully understood. In this review, we discuss how distinct subsets of CD4+ T cells metabolically adapt to the conditions of inflammation and whether these insights may pave the way to new treatments for human inflammatory diseases.

Diarylheptanoid from rhizomes of Curcuma kwangsiensis (DCK) inhibited imiquimod-induced dendritic cells activation and Th1/Th17 differentiation

Background and objectDendritic cells (DCs) are critical for initiating the activation and differentiation of T cells in inflammatory diseases including psoriasis. Curcuma kwangsiensis S.G. Lee & C.F. Liang is a herb for treating psoriasis and we previously found Diarylheptanoid from rhizomes of Curcuma kwangsiensis (DCK) inhibited keratinocytes proliferation. However, it is unknown whether DCK influences DC functions. Thus we aimed to explore whether DCK affect the major immunological functions of DCs. Materials and methodsPrimary DCs derived from mouse bone marrow cells and spleen were used for examining their general immunological functions, and OVA-specific T cells from OT-II mice were used for examining the DC-mediated T-helper (Th) 1 and Th17 cells differentiation and effect. ResultsWe demonstrated DCK suppressed DC uptake of FITC-labeled ovalbumin (OVA) and DC maturation characterized by decreased MHCII, CD80 and CD86 following imiquimod (IMQ) stimulation. DCK also reduced DC expression of the lymphoid-homing chemokine receptor CCR7, and DC migration towards CCL21, the ligand for CCR7. Importantly, DCK significantly reduced the production of proinflammatory cytokines including IL-12, IL-6 and IL-1β by IMQ-stimulated DCs. Moreover, in the coculture of OVA323–339 peptide-pulsed DCs and OVA-specific T cells from OT-II mice, DCK significantly inhibited T cell proliferation and the differentiation of Th1 and Th17 cells. Furthermore, DCK treatment greatly reduced phosphorylation of p65-associated cell signaling pathway in IMQ-stimulated DCs. ConclusionThese data together demonstrate a potential role of DCK in suppressing the biological function of DCs, and provide a possible mechanism for understanding the effects of herb Curcuma kwangsiensis in treating psoriasis.

Selective liposome targeting of folate receptor positive immune cells in inflammatory diseases

Activated macrophages play a key role in the development and maintenance of inflammatory diseases such as atherosclerosis, lupus, psoriasis, rheumatoid arthritis, ulcerative colitis, and many others. These activated macrophages, but not resting or quiescent macrophages highly up-regulate folate receptor beta (FR-β). This differential expression of FR-β provides a mechanism to selectively deliver imaging and therapeutic agents utilizing folate as a targeting molecule. In an effort to determine whether inflammatory diseases can be targeted utilizing a folate-linked nanosize carrier, a PEG-coated liposome was prepared that incorporated a folate conjugated PEG that also could transport imaging or therapeutic cargo. We demonstrate that these folate-liposomes specifically bind to folate receptor positive cells and accumulate at sites of inflammation in mouse models of colitis and atherosclerosis. These two animal models show that folate-targeted liposomes could be successfully utilized to deliver fluorescent molecules and an anti-inflammatory drug (betamethasone) for diagnostic and therapeutic applications.