Relationship Between the Lipidome Profile and Disease Activity in Patients with Rheumatoid Arthritis.

Lipid mediators have been suggested to play important roles in the pathogenesis of rheumatoid arthritis (RA). Lipidomics has recently allowed for the comprehensive analysis of lipids and has revealed the potential of lipids as biomarkers for the early diagnosis of RA and prediction of therapeutic responses. However, the relationship between disease activity and the lipid profile in RA remains unclear. In the present study, we performed a plasma lipidomic analysis of 278 patients with RA during treatment and examined relationships with disease activity using the Disease Activity Score in 28 joints (DAS28)-erythrocyte sedimentation rate (ESR). In all patients, five lipids positively correlated and seven lipids negatively correlated with DAS28-ESR. Stearic acid [FA(18:0)] (r = -0.45) and palmitic acid [FA(16:0)] (r = -0.38) showed strong negative correlations. After adjustments for age, body mass index (BMI), and medications, stearic acid, palmitic acid, bilirubin, and lysophosphatidylcholines negatively correlated with disease activity. Stearic acid inhibited osteoclast differentiation from peripheral blood monocytes in in vitro experiments, suggesting its contribution to RA disease activity by affecting bone metabolism. These results indicate that the lipid profile correlates with the disease activity of RA and also that some lipids may be involved in the pathogenesis of RA.

Corrigendum: Senescence of alveolar epithelial cells impacts initiation and chronic phases of murine fibrosing interstitial lung disease.

[This corrects the article DOI: 10.3389/fimmu.2022.935114.].

Senescence of alveolar epithelial cells impacts initiation and chronic phases of murine fibrosing interstitial lung disease.

Fibrosing interstitial lung disease (ILD) develops due to the impaired reparative processes following lung tissue damage. Cellular senescence has been reported to contribute to the progression of fibrosis. However, the mechanisms by which these senescent cells initiate and/or drive the progression of lung tissue fibrosis are not yet fully understood. We demonstrated that p21WAF1/CIP1- and p16INK4A-pathway-dependent senescence in type 2 alveolar epithelial cells (AEC2) were both involved in the initiation and progression of lung fibrosis in murine bleomycin (BLM)-induced ILD. p21WAF1/CIP1-senescent AEC2 emerged rapidly, as early as 1 day after the intratracheal instillation of BLM. Their number subsequently increased and persisted until the later fibrosis phase. Very few p16INK4A-senescent AEC2 emerged upon the instillation of BLM, and their increase was slower and milder than that of p21WAF1/CIP1+ AEC2. AEC2 enriched with senescent cells sorted from BLM-ILD lungs expressed senescence-associated secretory phenotype (SASP)-related genes, including Il6, Serpin1, Tnfa, Ccl2, Tgfb, and Pdgfa, at the initiation and chronic phases of fibrosis, exhibiting distinct expression patterns of magnitude that were dependent on the disease phase. Ly6C+ inflammatory monocytes increased in the lungs immediately after the instillation of BLM and interstitial macrophages increased from day 3. The expression of Acta2 and Col1a1 was upregulated as early as day 1, indicating the activation of fibroblasts. We speculated that IL-6, plasminogen activator inhibitor-1 (PAI-1), and TGF-ß contributed to the accumulation of senescent cells during the progression of fibrosis in an autocrine and paracrine manner. In addition, CCL2, produced in large amounts by senescent AEC2, may have induced the infiltration of Ly6C+ inflammatory monocytes in the early phase, and TGF-ß and PDGFa from senescent AEC2 may contribute to the activation of fibroblasts in the very early phases. Our study indicated that senescent AEC2 plays a role in the pathogenesis of fibrosing ILD throughout the course of the disease and provides insights into its pathogenesis, which may lead to the development of new therapeutic methods targeting senescent cells or SASP molecules.

Evaluation of wiping edible sesame oils in the oral cavities of hospitalised older patients who resist oral hygiene management.

Context: One of the causes of aspiration pneumonia is poor oral hygiene. We need care methods that caregivers can quickly, safely and inexpensively implement for convalescents with inadequate self-care. Edible sesame oil containing sesamin or sesaminol has already been shown to inhibit bacterial and fungal growth and have a vasodilating effect. Aims: The aim of this study is to evaluate the usefulness of using edible sesame oils for oral hygiene management. Settings and Design: This study evaluates an oral hygiene management method using two types of sesame oils in elderly hospitalised patients resistant to oral hygiene management. Methods and Material: The inpatients received oral care for 90 days. In the intervention groups, nurses brushed and wiped the oral cavity with roasted sesame oil (RSO) or sesame salad oil, while in the control group, care with tap water alone and brushing were done. Bacteria and Candida counts from tongue swabs, water content from the tongue's surface and cheek mucosa, oral health assessment tool (OHAT) and cytology of the cheek mucosa were assessed every 30 days before and after the intervention. Results: RSO showed a tendency to reduce the number of bacteria and Candida. There was an improvement in the OHAT scores with both oils. The water content or cytology was not changing. Conclusions: Sesame oils may improve oral hygiene and maintain health in older patients.

Identification and characterization of a novel Enterococcus bacteriophage with potential to ameliorate murine colitis.

Increase of the enteric bacteriophages (phage), components of the enteric virome, has been associated with the development of inflammatory bowel diseases. However, little is known about how a given phage contributes to the regulation of intestinal inflammation. In this study, we isolated a new phage associated with Enterococcus gallinarum, named phiEG37k, the level of which was increased in C57BL/6 mice with colitis development. We found that, irrespective of the state of inflammation, over 95% of the E. gallinarum population in the mice contained phiEG37k prophage within their genome and the phiEG37k titers were proportional to that of E. gallinarum in the gut. To explore whether phiEG37k impacts intestinal homeostasis and/or inflammation, we generated mice colonized either with E. gallinarum with or without the prophage phiEG37k. We found that the mice colonized with the bacteria with phiEG37k produced more Mucin 2 (MUC2) that serves to protect the intestinal epithelium, as compared to those colonized with the phage-free bacteria. Consistently, the former mice were less sensitive to experimental colitis than the latter mice. These results suggest that the newly isolated phage has the potential to protect the host by strengthening mucosal integrity. Our study may have clinical implication in further understanding of how bacteriophages contribute to the gut homeostasis and pathogenesis.

CX3CL1/fractalkine regulates the differentiation of human peripheral blood monocytes and monocyte-derived dendritic cells into osteoclasts.

Osteoclast differentiation is promoted under inflammatory conditions and osteoclasts play a major role in bone destruction in rheumatoid arthritis (RA). Chemokine (C-X3-C motif) ligand 1 (CX3CL1), also known as fractalkine, functions as a chemoattractant and adhesion molecule, and is involved in the pathogenesis of RA. The blockade of CX3CL1 inhibits the migration of macrophages and osteoclast precursor cells into the inflamed synovium. In the present study, we investigated the direct stimulatory effects of CX3CL1 on osteoclast differentiation from human peripheral blood monocytes and monocyte-derived dendritic cells. A stimulation with CX3CL1 significantly promoted osteoclast differentiation from CD16- monocytes and also monocyte-derived dendritic cells induced by macrophage colony-stimulating factor (M-CSF) and receptor activator of NF-κB ligand (RANKL). On the other hand, CD16+ monocytes treated with M-CSF and RANKL did not differentiate into osteoclasts, even with CX3CL1. Calcium resorption was significantly increased by monocyte-derived osteoclasts, but not by dendritic cell-derived osteoclasts, following the addition of CX3CL1. The present results suggest that CX3CL1 directly regulates osteoclast differentiation. CX3CL1 may play important roles in the pathogenesis of RA, not only through the accumulation of inflammatory cells, but also through osteoclastogenesis.

Treatment with an Anti-CX3CL1 Antibody Suppresses M1 Macrophage Infiltration in Interstitial Lung Disease in SKG Mice.

CX3C Motif Chemokine Ligand 1 (CX3CL1; fractalkine) has been implicated in the pathogenesis of rheumatoid arthritis (RA) and its inhibition was found to attenuate arthritis in mice as well as in a clinical trial. Therefore, we investigated the effects of an anti-CX3CL1 monoclonal antibody (mAb) on immune-mediated interstitial lung disease (ILD) in SKG mice, which exhibit similar pathological and clinical features to human RA-ILD. CX3CL1 and CX3C chemokine receptor 1 (CX3CR1), the receptor for CX3CL1, were both expressed in the fibroblastic foci of lung tissue and the number of bronchoalveolar fluid (BALF) cells was elevated in ILD in SKG mice. No significant changes were observed in lung fibrosis or the number of BALF cells by the treatment with anti-CX3CL1 mAb. However, significantly greater reductions were observed in the number of M1 macrophages than in M2 macrophages in the BALF of treated mice. Furthermore, CX3CR1 expression levels were significantly higher in M1 macrophages than in M2 macrophages. These results suggest the stronger inhibitory effects of the anti-CX3CL1 mAb treatment against the alveolar infiltration of M1 macrophages than M2 macrophages in ILD in SKG mice. Thus, the CX3CL1-CX3CR1 axis may be involved in the infiltration of inflammatory M1 macrophages in RA-ILD.

HMGB1-mediated chromatin remodeling attenuates Il24 gene expression for the protection from allergic contact dermatitis.

Dysregulation of inflammatory cytokines in keratinocytes promote the pathogenesis of the skin inflammation, such as allergic contact dermatitis (ACD). High-mobility group box 1 protein (HMGB1) has been implicated in the promotion of skin inflammation upon its extracellular release as a damage-associated molecular pattern molecule. However, whether and how HMGB1 in keratinocytes contributes to ACD and other skin disorders remain elusive. In this study, we generated conditional knockout mice in which the Hmgb1 gene is specifically deleted in keratinocytes, and examined its role in ACD models. Interestingly, the mutant mice showed exacerbated skin inflammation, accompanied by increased ear thickening in 2,4-dinitrofluorobenezene-induced ACDs. The mRNA expression of interleukin-24 (IL-24), a cytokine known to critically contribute to ACD pathogenesis, was elevated in skin lesions of the mutant mice. As with constitutively expressed, IL-4-induced Il24 mRNA, expression was also augmented in the Hmgb1-deficient keratinocytes, which would account for the exacerbation of ACD in the mutant mice. Mechanistically, we observed an increased binding of trimethyl histone H3 (lys4) (H3K4me3), a hallmark of transcriptionally active genes, to the promoter region of the Il24 gene in the hmgb1-deficient cells. Thus, the nuclear HMGB1 is a critical "gate keeper" in that the dermal homeostasis is contingent to its function in chromatin remodeling. Our study revealed a facet of nuclear HMGB1, namely its antiinflammatory function in keratinocytes for the skin homeostasis.

Rationale for and clinical development of anti-fractalkine antibody in rheumatic diseases.

Introduction: Rheumatic diseases are inflammatory diseases that damage target organs via multiple subsets of immune cells. Fractalkine (FKN) acts as chemoattractant as well as adhesion molecule. It contributes to the pathogenesis of rheumatoid arthritis (RA) and other rheumatic diseases through multiple mechanisms: the migration of monocytes and cytotoxic effector T cells, the proliferation and activation of fibroblast-like synoviocytes, angiogenesis, and osteoclastogenesis. FKN has potential as a new therapeutic target, and clinical trials on anti-FKN monoclonal antibodies for RA are ongoing. FKN-targeted therapy has been developed and a humanized anti-FKN monoclonal antibody is currently being tested in phase 2 clinical trials. Areas covered: This review summarizes accumulated evidence on the involvement of FKN in RA and other rheumatic diseases, including systemic lupus erythematosus (SLE), systemic sclerosis, inflammatory myositis, Sjögren's syndrome (SS), osteoarthritis, and systemic vasculitis. Expert opinion: A phase 1/2a clinical trial on anti-FKN demonstrated its safety, tolerability, and clinical efficacy. Anti-FKN therapy has potential in the treatment of atherosclerosis and interstitial lung diseases associated with RA. Based on recent findings, other rheumatic diseases, including SLE, polymyositis/dermatomyositis, and SS, may also be treated using anti-FKN therapy.

Effect of using portable alcohol-based handrub on nurses' hand hygiene compliance and nasal carriage of staphylococcus aureus in a low-income health setting.

BACKGROUND: Low hand-hygiene compliance (HHC) in low-income countries due to deficient hand hygiene resources may increase nasal carriage of S. aureus, a causative agent of health care-associated infections. The study aimed to assess the effect of using locally available portable alcohol-based handrub (ABHR) regarding nurses' HHC and nasal carriage of S. aureus. METHODS AND DESIGN: Nonrandomized interventional design. Seventy-two (72) of 86 nurses were provided with portable ABHR to use during patient care (intervention group). The remaining 14 nurses constituted the control group. Evaluation was done via HHC observation per WHO 5-moments of HH, determining S. aureus nasal carriage prevalence and HH guideline knowledge assessment via a self-response questionnaire. RESULTS: In the intervention group, HHC improved from 48.9% to 67.7% (P < .001) especially for hand-hygiene before and after patient contact. Hand-hygiene by handrubbing improved from 16 to 105 moments. There was positive feedback to portable ABHR use from nurses. S. aureus nasal carriage significantly decreased from 30.6% to 21% (P < .031). Negative carriage of S. aureus was significantly associated with increase in HHC (P < .001). Despite the low preintervention HHC, nurses showed considerably high levels of knowledge on relevance of hand hygiene. CONCLUSIONS: Portable ABHR use was associated with improved HHC and reduced S. aureus nasal carriage prevalence. As nurses' knowledge of HH guidelines was high, provision of portable ABHR compensated for deficient facility HH resources resulting in improved HHC, which effected reduction in nasal carriage of S. aureus among nurses.

Identification of U11snRNA as an endogenous agonist of TLR7-mediated immune pathogenesis.

The activation of innate immune receptors by pathogen-associated molecular patterns (PAMPs) is central to host defense against infections. On the other hand, these receptors are also activated by immunogenic damage-associated molecular patterns (DAMPs), typically released from dying cells, and the activation can evoke chronic inflammatory or autoimmune disorders. One of the best known receptors involved in the immune pathogenesis is Toll-like receptor 7 (TLR7), which recognizes RNA with single-stranded structure. However, the causative DAMP RNA(s) in the pathogenesis has yet to be identified. Here, we first developed a chemical compound, termed KN69, that suppresses autoimmunity in several established mouse models. A subsequent search for KN69-binding partners led to the identification of U11 small nuclear RNA (U11snRNA) as a candidate DAMP RNA involved in TLR7-induced autoimmunity. We then showed that U11snRNA robustly activated the TLR7 pathway in vitro and induced arthritis disease in vivo. We also found a correlation between high serum level of U11snRNA and autoimmune diseases in human subjects and established mouse models. Finally, by revealing the structural basis for U11snRNA's ability to activate TLR7, we developed more potent TLR7 agonists and TLR7 antagonists, which may offer new therapeutic approaches for autoimmunity or other immune-driven diseases. Thus, our study has revealed a hitherto unknown immune function of U11snRNA, providing insight into TLR7-mediated autoimmunity and its potential for further therapeutic applications.

Novel chemical compound SINCRO with dual function in STING-type I interferon and tumor cell death pathways.

Recent years have seen a number of regulatory approvals for immune oncology or immunotherapies based on their ability to enhance antitumor immune responses. Nevertheless, the majority of patients remain refractory to these treatments; hence, new therapies that augment current immunotherapies are required. Innate immune receptors that recognize nucleic acids are potent activators of subsequent T-cell responses and, as a result, can evoke potent antitumor immune responses. Herein, we present a novel compound N-{3-[(1,4'-bipiperidin)-1'-yl]propyl}-6-[4-(4-methylpiperazin-1-yl)phenyl]picolinamide (SINCRO; STING-mediated interferon-inducing and cytotoxic reagent, original) as an anticancer drug that activates the cytosolic DNA-sensing STING (stimulator of interferon genes) signaling pathway leading to the induction of type I interferon (IFN) genes. Indeed, IFN-ß gene induction by SINCRO is abolished in STING-deficient cells. In addition to its IFN-inducing activity, SINCRO shows STING-independent cytotoxic activity against cancer cells. SINCRO does not evoke DNA double-strand break or caspase-3 cleavage. Thus, SINCRO induces cell death in a method different from conventional apoptosis-inducing pathways. Finally, we provide evidence that giving SINCRO significantly attenuates in vivo tumor growth by both type I IFN-dependent and independent mechanisms. Thus, SINCRO is an attractive anticancer compound with dual function in that it evokes type I IFN response to promote antitumor immunity as well as inducing tumor cell death. SINCRO may provide a new platform for the development of drugs for effective cancer therapy.

Revisiting the role of IRF3 in inflammation and immunity by conditional and specifically targeted gene ablation in mice.

IFN regulatory factor 3 (IRF3) is a transcription regulator of cellular responses in many cell types that is known to be essential for innate immunity. To confirm IRF3's broad role in immunity and to more fully discern its role in various cellular subsets, we engineered Irf3-floxed mice to allow for the cell type-specific ablation of Irf3 Analysis of these mice confirmed the general requirement of IRF3 for the evocation of type I IFN responses in vitro and in vivo. Furthermore, immune cell ontogeny and frequencies of immune cell types were unaffected when Irf3 was selectively inactivated in either T cells or B cells in the mice. Interestingly, in a model of lipopolysaccharide-induced septic shock, selective Irf3 deficiency in myeloid cells led to reduced levels of type I IFN in the sera and increased survival of these mice, indicating the myeloid-specific, pathogenic role of the Toll-like receptor 4-IRF3 type I IFN axis in this model of sepsis. Thus, Irf3-floxed mice can serve as useful tool for further exploring the cell type-specific functions of this transcription factor.

Gallbladder-derived surfactant protein D regulates gut commensal bacteria for maintaining intestinal homeostasis.

The commensal microbiota within the gastrointestinal tract is essential in maintaining homeostasis. Indeed, dysregulation in the repertoire of microbiota can result in the development of intestinal immune-inflammatory diseases. Further, this immune regulation by gut microbiota is important systemically, impacting health and disease of organ systems beyond the local environment of the gut. What has not been explored is how distant organs might in turn shape the microbiota via microbe-targeted molecules. Here, we provide evidence that surfactant protein D (SP-D) synthesized in the gallbladder and delivered into intestinal lumen binds selectively to species of gut commensal bacteria. SP-D-deficient mice manifest intestinal dysbiosis and show a susceptibility to dextran sulfate sodium-induced colitis. Further, fecal transfer from SP-D-deficient mice to wild-type, germ-free mice conveyed colitis susceptibility. Interestingly, colitis caused a notable increase in Sftpd gene expression in the gallbladder, but not in the lung, via the activity of glucocorticoids produced in the liver. These findings describe a unique mechanism of interorgan regulation of intestinal immune homeostasis by SP-D with potential clinical implications such as cholecystectomy.

The innate immune receptor Dectin-2 mediates the phagocytosis of cancer cells by Kupffer cells for the suppression of liver metastasis.

Tumor metastasis is the cause of most cancer deaths. Although metastases can form in multiple end organs, the liver is recognized as a highly permissive organ. Nevertheless, there is evidence for immune cell-mediated mechanisms that function to suppress liver metastasis by certain tumors, although the underlying mechanisms for the suppression of metastasis remain elusive. Here, we show that Dectin-2, a C-type lectin receptor (CLR) family of innate receptors, is critical for the suppression of liver metastasis of cancer cells. We provide evidence that Dectin-2 functions in resident macrophages in the liver, known as Kupffer cells, to mediate the uptake and clearance of cancer cells. Interestingly, Kupffer cells are selectively endowed with Dectin-2-dependent phagocytotic activity, with neither bone marrow-derived macrophages nor alveolar macrophages showing this potential. Concordantly, subcutaneous primary tumor growth and lung metastasis are not affected by the absence of Dectin-2. In addition, macrophage C-type lectin, a CLR known to be complex with Dectin-2, also contributes to the suppression of liver metastasis. Collectively, these results highlight the hitherto poorly understood mechanism of Kupffer cell-mediated control of metastasis that is mediated by the CLR innate receptor family, with implications for the development of anticancer therapy targeting CLRs.

PGE2 induced in and released by dying cells functions as an inhibitory DAMP.

Cellular components released into the external milieu as a result of cell death and sensed by the body are generally termed damage-associated molecular patterns (DAMPs). Although DAMPs are conventionally thought to be protective to the host by evoking inflammatory responses important for immunity and wound repair, there is the prevailing notion that dysregulated release of DAMPs can also underlie or exacerbate disease development. However, the critical issue for how resultant DAMP-mediated responses are regulated has heretofore not been fully addressed. In the present study, we identify prostaglandin E2 (PGE2) as a DAMP that negatively regulates immune responses. We show that the production of PGE2 is augmented under cell death-inducing conditions via the transcriptional induction of the cyclooxygenase 2 (COX2) gene and that cell-released PGE2 suppresses the expression of genes associated with inflammation, thereby limiting the cell's immunostimulatory activities. Consistent with this, inhibition of the PGE2 synthesis pathway potentiates the inflammation induced by dying cells. We also provide in vivo evidence for a protective role of PGE2 released upon acetaminophen-induced liver injury as well as a pathogenic role for PGE2 during tumor cell growth. Our study places this classically known lipid mediator in an unprecedented context-that is, an inhibitory DAMP vis-à-vis activating DAMPs, which may have translational implications for designing more effective therapeutic regimens for inflammation-associated diseases.

Requirement of full TCR repertoire for regulatory T cells to maintain intestinal homeostasis.

The regulation of intestinal homeostasis by the immune system involves the dynamic interplay between gut commensal microbiota and resident immune cells. It is well known that a large and diverse lymphocyte antigen receptor repertoire enables the immune system to recognize and respond to a wide range of invading pathogens. There is also an emerging appreciation for a critical role the T-cell receptor (TCR) repertoire serves in the maintenance of peripheral tolerance by regulatory T cells (Tregs). Nevertheless, how the diversity of the TCR repertoire in Tregs affects intestinal homeostasis remains unknown. To address this question, we studied mice whose T cells express a restricted TCR repertoire. We observed the development of spontaneous colitis, accompanied by the induction of T-helper type 17 cells in the colon that is driven by gut commensal microbiota. We provide further evidence that a restricted TCR repertoire causes a loss of tolerogenicity to microbiota, accompanied by a paucity of peripherally derived, Helios(-) Tregs and hyperactivation of migratory dendritic cells. These results thus reveal a new facet of the TCR repertoire in which Tregs require a diverse TCR repitoire for intestinal homeostasis, suggesting an additional driving force in the evolutional significance of the TCR repertoire.

Recognition of tumor cells by Dectin-1 orchestrates innate immune cells for anti-tumor responses.

The eradication of tumor cells requires communication to and signaling by cells of the immune system. Natural killer (NK) cells are essential tumor-killing effector cells of the innate immune system; however, little is known about whether or how other immune cells recognize tumor cells to assist NK cells. Here, we show that the innate immune receptor Dectin-1 expressed on dendritic cells and macrophages is critical to NK-mediated killing of tumor cells that express N-glycan structures at high levels. Receptor recognition of these tumor cells causes the activation of the IRF5 transcription factor and downstream gene induction for the full-blown tumoricidal activity of NK cells. Consistent with this, we show exacerbated in vivo tumor growth in mice genetically deficient in either Dectin-1 or IRF5. The critical contribution of Dectin-1 in the recognition of and signaling by tumor cells may offer new insight into the anti-tumor immune system with therapeutic implications.

Effect of edible sesame oil on growth of clinical isolates of Candida albicans.

Elderly individuals are at increased risk of oral thrush (oral candidiasis) due to decreased saliva secretion. Due to their antimicrobial properties, edible oils can be effective natural agents for oral care. The objective of the present study was to compare the effects of sesame oil, which is widely used for cooking in Asian countries, and two other edible oils on the growth of both mycelial and yeast forms of five clinical isolates of Candida albicans, a causative microorganism of oral thrush. We assessed the effect of each oil in concentrations of 0.078%, 0.156%, and 0.313% on growth of the mycelial forms of the clinical isolates over 24 hr using the crystal violet method. We also evaluated the effect of each oil on growth of the yeast forms by counting the number of viable yeast cells after culturing in the oils for 24 hr. Sesame oil inhibited the growth of both mycelial and yeast forms. Safflower and olive oil also inhibited the growth of both forms of C. albicans but to a lesser extent than sesame oil. The ability to inhibit the growth of the mycelial form correlated with sesame oil concentration. Roasting influenced growth inhibition ability and high-roasted sesame oil most effectively inhibited the yeast form. The growth inhibitory effect differed among the five isolates. We hypothesize that the sesamin and fatty acid components of sesame oil are involved in its antifungal activity.