Identification of memory mechanism in tissue-resident stem cells via ANGPTL4 beyond immune cells upon viral antigen exposure.

Although memory functions of immune cells characterized by increased resistance to subsequent infections after initial pathogen exposure are well-established, it remains unclear whether non-immune cells, especially tissue-resident stem cells, exhibit similar memory mechanisms. The present study revealed that detrimental effects of initial viral antigen exposure (human papillomavirus [HPV]) on diverse stem cell functions were significantly exacerbated upon subsequent secondary exposure both in vitro and in vivo. Importantly, endometrial stem cells exhibited robust memory functions following consecutive HPV antigen exposures, whereas fully differentiated cells such as fibroblasts and vesicular cells did not show corresponding changes in response to the same antigen exposures. Deficiency of angiopoietin-like 4 (ANGPTL4) achieved through small hairpin RNA knockdown in vitro and knockout (KO) mice in vivo highlighted the critical role of ANGPTL4 in governing memory functions associated with various stem cell processes. This regulation occurred through histone H3 methylation alterations and PI3K/Akt signaling pathways in response to successive HPV antigen exposures. Furthermore, memory functions associated with various stem cell functions that were evident in wild-type mice following consecutive exposures to HPV antigen were not observed in ANGPTL4 KO mice. In summary, our findings strongly support the presence of memory mechanism in non-immune cells, particularly tissue-resident stem cells.

Osteopontin is a key regulator of vascular smooth muscle cell proliferation in the outflow vein of arteriovenous fistulas.

OBJECTIVES: Despite advances in the maintenance of arteriovenous fistulas (AVFs), the patency rates remain suboptimal. Most AVFs fail due to outflow vein stenosis; however, the underlying mechanism of AVF stenosis remains unclear. The present study aimed to identify key factors associated with AVF outflow stenosis. METHODS: We obtained gene expression profiling data for the outflow vein of AVF from three Gene Expression Omnibus database datasets (GSE39488, GSE97377, and GSE116268) and analyzed the common differentially expressed genes (DEGs). We evaluated a common DEG in an aortocaval mouse model and the stenotic outflow veins of AVFs collected from patients. Furthermore, we isolated vascular smooth muscle cells (VSMCs) from the inferior vena cava (IVC) of wild-type (WT) and osteopontin (Opn)-knockout (KO) mice and assessed the proliferation of VSMCs following stimulation with platelet-derived growth factors (PDGFs). RESULTS: OPN was the only common upregulated DEG among all datasets. OPN was expressed in the medial layer of the outflow vein of AVF in aortocaval mouse models and co-stained with the VSMC marker (α-smooth muscle actin). OPN expression was markedly increased in the VSMCs of stenotic outflow veins of AVF collected from patients undergoing hemodialysis compared to presurgical veins acquired during AVF formation surgery. PDGF-induced VSMC proliferation was significantly increased in the VSMCs isolated from the IVC of WT mice but not in those isolated from the IVC of Opn-KO mice. CONCLUSIONS: OPN may be a key gene involved in VSMC proliferation in the AVF outflow veins and a therapeutic target to improve the AVF patency rate.

Unveiling the potential effects of acetylsalicylic acid: insights into regeneration in endometrial stem cells.

BACKGROUND: Although acetylsalicylic acid has been widely used for decades to treat and prevent various diseases, its potential effects on endometrial receptivity and subsequent pregnancy rates are still controversial due to conflicting data: many reports have shown positive effects of acetylsalicylic acid, whereas others have found that it has no effect. Furthermore, the direct effects of acetylsalicylic acid on various functions of normal endometrial cells, especially endometrial stem cells, and their underlying molecular mechanisms have not yet been proven. Recently, studies have revealed that a reduced number of active stem/progenitor cells within endometrial tissue limits cyclic endometrial regeneration and subsequently decreases pregnancy success rates, suggesting that endometrial stem cells play a critical role in endometrial regeneration and subsequent endometrial receptivity. METHODS: We assessed whether aspirin treatment can inhibit various endometrial stem cell functions related to regenerative capacity, such as self-renewal, migration, pluripotency/stemness, and differentiation capacity, in vitro. Next, we evaluated whether SERPINB2 regulates the effects of aspirin on endometrial stem cell functions by depleting SERPINB2 expression with specific shRNA targeting SERPINB2. To further investigate whether aspirin also inhibits various endometrial stem cell functions in vivo, aspirin was administered daily to mice through intraperitoneal (i.p.) injection for 7 days. RESULTS: In addition to its previously identified roles, to the best of our knowledge, we found for the first time that acetylsalicylic acid directly inhibits various human endometrial stem cell functions related to regenerative capacity (i.e., self-renewal, migration, differentiation, and capacity) through its novel target gene SERPINB2 in vitro. Acetylsalicylic acid exerts its function by suppressing well-known prosurvival pathways, such as Akt and/or ERK1/2 signaling, through a SERPINB2 signaling cascade. Moreover, we also found that acetylsalicylic acid markedly inhibits regenerative capacity-related functions in endometrial stem cells within tissue. CONCLUSIONS: We have found that acetylsalicylic acid has diverse effects on various endometrial stem cell functions related to regenerative capacity. Our findings are a critical step toward the development of more effective therapeutic strategies to increase the chances of successful pregnancy. Video Abstract.

Fructose malabsorption in ChREBP-deficient mice disrupts the small intestine immune microenvironment and leads to diarrhea-dominant bowel habit changes.

BACKGROUND: The mechanism by which incompletely absorbed fructose causes gastrointestinal symptoms is not fully understood. In this study, we investigated the immunological mechanisms of bowel habit changes associated with fructose malabsorption by examining Chrebp-knockout mice exhibiting defective fructose absorption. METHODS: Mice were fed a high-fructose diet (HFrD), and stool parameters were monitored. The gene expression in the small intestine was analyzed by RNA sequencing. Intestinal immune responses were assessed. The microbiota composition was determined by 16S rRNA profiling. Antibiotics were used to assess the relevance of microbes for HFrD-induced bowel habit changes. RESULTS: Chrebp-knockout (KO) mice fed HFrD showed diarrhea. Small-intestine samples from HFrD-fed Chrebp-KO mice revealed differentially expressed genes involved in the immune pathways, including IgA production. The number of IgA-producing cells in the small intestine decreased in HFrD-fed Chrebp-KO mice. These mice showed signs of increased intestinal permeability. Chrebp-KO mice fed a control diet showed intestinal bacterial imbalance, which the HFrD exaggerated. Bacterial reduction improved diarrhea-associated stool parameters and restored the decreased IgA synthesis induced in HFrD-fed Chrebp-KO mice. CONCLUSIONS: The collective data indicate that gut microbiome imbalance and disrupting homeostatic intestinal immune responses account for the development of gastrointestinal symptoms induced by fructose malabsorption.

Polar microalgae extracts protect human HaCaT keratinocytes from damaging stimuli and ameliorate psoriatic skin inflammation in mice.

BACKGROUND: Polar microalgae contain unique compounds that enable them to adapt to extreme environments. As the skin barrier is our first line of defense against external threats, polar microalgae extracts may possess restorative properties for damaged skin, but the potential of microalgae extracts as skin protective agents remains unknown. PURPOSE: This study aimed to analyze compound profiles from polar microalgae extracts, evaluate their potential as skin epithelial protective agents, and examine the underlying mechanisms. METHODS: Six different polar microalgae, Micractinium sp. (KSF0015 and KSF0041), Chlamydomonas sp. (KNM0029C, KSF0037, and KSF0134), and Chlorococcum sp. (KSF0003), were collected from the Antarctic or Arctic regions. Compound profiles of polar and non-polar microalgae extracts were analyzed using gas chromatography-mass spectrometry (GC-MS). The protective activities of polar microalgae extracts on human keratinocyte cell lines against oxidative stress, radiation, and psoriatic cytokine exposure were assessed. The potential anti-inflammatory mechanisms mediated by KSF0041, a polar microalga with protective properties against oxidative stress, ultraviolet (UV) B, and an inflammatory cytokine cocktail, were investigated using RNA-sequencing analysis. To evaluate the therapeutic activity of KSF0041, an imiquimod-induced murine model of psoriatic dermatitis was used. RESULTS: Polar microalgae contain components comparable to those of their non-polar counterparts, but also showed distinct differences, particularly in fatty acid composition. Polar microalgae extracts had a greater ability to scavenge free radicals than did non-polar microalgae and enhanced the viability of HaCaT cells, a human keratinocyte cell line, following exposure to UVB radiation or psoriatic cytokines. These extracts also reduced barrier integrity damage and decreased mRNA levels of inflammatory cytokines in psoriatic HaCaT cells. Treatment with KSF0041 extract altered the transcriptome of psoriatic HaCaT cells toward a more normal state. Furthermore, KSF0041 extract had a therapeutic effect in a mouse model of psoriasis. CONCLUSIONS: Bioactive compounds from polar microalgae extracts could provide novel therapeutics for damaged and/or inflamed skin.

Antarctic Marine Algae Extracts as a Potential Natural Resource to Protect Epithelial Barrier Integrity.

The intestine and skin provide crucial protection against the external environment. Strengthening the epithelial barrier function of these organs is critical for maintaining homeostasis against inflammatory stimuli. Recent studies suggest that polar marine algae are a promising bioactive resource because of their adaptation to extreme environments. To investigate the bioactive properties of polar marine algae on epithelial cells of the intestine and skin, we created extracts of the Antarctic macroalgae Himantothallus grandifolius, Plocamium cartilagineum, Phaeurus antarcticus, and Kallymenia antarctica, analyzed the compound profiles of the extracts using gas chromatography-mass spectrometry, and tested the protective activities of the extracts on human intestinal and keratinocyte cell lines by measuring cell viability and reactive oxygen species scavenging. In addition, we assessed immune responses modulated by the extracts by real-time polymerase chain reaction, and we monitored the barrier-protective activities of the extracts on intestinal and keratinocyte cell lines by measuring transepithelial electrical resistance and fluorescence-labeled dextran flux, respectively. We identified bioactive compounds, including several fatty acids and lipid compounds, in the extracts, and found that the extracts perform antioxidant activities that remove intracellular reactive oxygen species and scavenge specific radicals. Furthermore, the Antarctic marine algae extracts increased cell viability, protected cells against inflammatory stimulation, and increased the barrier integrity of cells damaged by lipopolysaccharide or ultraviolet radiation. These results suggest that Antarctic marine algae have optimized their composition for polar environments, and furthermore, that the bioactive properties of compounds produced by Antarctic marine algae can potentially be used to develop therapeutics to promote the protective barrier function of the intestine and skin.

Expression pattern of tissue-resident memory T cells in cutaneous lupus erythematosus.

BACKGROUND: Tissue resident memory T cells (TRMs) persist long-term in peripheral tissues without recirculation, triggering an immediate protective inflammatory state upon the re-recognition of the antigen. Despite evidence incriminating the dysregulation of TRMs in autoimmune diseases, few studies have examined their expression in cutaneous lupus erythematosus (CLE). OBJECTIVES: We aimed to examine whether there are differences among TRM populations in CLE depending on different clinical conditions, such as the CLE subtype or association with systemic lupus erythematosus, and to determine the effect of type I interferon (IFN) on the development of TRMs in CLE. METHODS: CLE disease activity was evaluated using the Cutaneous Lupus Erythematosus Disease Area and Severity Index. The expression of the TRM markers CD69 and CD103 in CLE lesions was evaluated by immunofluorescence. Flow cytometry was performed on peripheral blood mononuclear cells after IFNα treatment. RESULTS: The number of TRMs expressing either CD69 or CD103 was significantly higher in CLE lesions than in control skin; however, it was not significantly different between discoid lupus erythematosus and subacute CLE, or dependent on the presence of concomitant systemic lupus. Lesional severity was not correlated with an increase in TRMs in CLE. IFNα treatment induced a conspicuous increase in CD69 expression in skin-homing T cells, more profoundly in CD4+ T cells than in CD8+ T cells. CONCLUSIONS: Skin TRMs, either CD69 or CD103-positive cells, showed increased levels in the lesional skin of CLE, and IFNα increased the expression of CD69 in T cells.

Association between the change of total cholesterol during adolescence and depressive symptoms in early adulthood.

Increasing evidence suggests that serum lipids are associated with depressive symptoms. However, previous studies have mostly employed a cross-sectional design and assessed middle-aged or older adult populations, making it difficult to discern the impact of lipid changes early in life on the development of depression. Accordingly, we sought to investigate changes in blood cholesterol levels during adolescence and the development of depressive symptoms in early adulthood. This prospective cohort study included participants aged 15-16 years from the JS High School Study (JSHS), with an average follow-up of 6 years. Participants had no diagnosed depression at baseline. Multivariable linear regression models were used to estimate associations between changes in total cholesterol during adolescence and depressive symptoms in adulthood. Changes in total cholesterol during adolescence were classified as "consistently low," "decreased," "moderate," "increased," or "consistently high". In men, depressive symptoms were higher in the consistently low (ß = 3.20, p = 0.036) and increased total cholesterol groups (ß = 3.48, p = 0.017), compared with the moderate group. In the consistently high group, although a positive linear association was observed, it lacked statistical significance (ß = 2.71, p = 0.067). While similar tendencies were noted in women, the associations were not statistically significant. Consistently low or increased total cholesterol levels during adolescence may pose an increased risk of depressive symptoms in early adulthood. These findings suggest that different strategies should be adopted to manage the lipid risk factors with consideration of age and sex.

Regulation of humoral and cellular gut immunity by lamina propria dendritic cells expressing Toll-like receptor 5.

The intestinal cell types responsible for defense against pathogenic organisms remain incompletely characterized. Here we identify a subset of CD11c(hi)CD11b(hi) lamina propria dendritic cells (LPDCs) that expressed Toll-like receptor 5 (TLR5) in the small intestine. When stimulated by the TLR5 ligand flagellin, TLR5(+) LPDCs induced the differentiation of naive B cells into immunoglobulin A-producing plasma cells by a mechanism independent of gut-associated lymphoid tissue. In addition, by a mechanism dependent on TLR5 stimulation, these LPDCs promoted the differentiation of antigen-specific interleukin 17-producing T helper cells and type 1 T helper cells. Unlike spleen DCs, the LPDCs specifically produced retinoic acid, which, in a dose-dependent way, supported the generation and retention of immunoglobulin A-producing cells in the lamina propria and positively regulated the differentiation interleukin 17-producing T helper cells. Our findings demonstrate unique properties of LPDCs and the importance of TLR5 for adaptive immunity in the intestine.

Clinical Impact of PD-L1 Expression for Survival in Curatively Resected Colon Cancer.

BACKGROUND: Programmed death 1 (PD-1) and its ligand PD-L1 play a key dysfunction of T lymphocytes. The purpose of this study was to assess and compare the prognostic role of tumor- TILs and its relationship with PD-L1 expression in stage II and III colon cancer. METHODS: Immunohistochemisty was used to assess the densities of CD8+, CD4+, and FOXP3+ cells, and PD-L1 expression in intraepithelial tumor site from 58 stage II and III colon cancers. These were evaluated for association with histopathologic features and overall survival. RESULTS: PD-L1-positive tumors contained a higher number of CD8+ TILs with statistical significance (p = 0.001). CD4+ TILs showed positive correlation with PD-L1 expression (p = 0.034). There were no associations between PD-L1 expression and FOXP3+ TILs. Microsatellite instability (MSI)-high status (p = 0.001; Odd ration 18.0; 95% CI = 4.3-74.8) was the strongest prognostic factor along with mucinous/poor cell differentiation, CD8 and right tumor location was associated with PD-L1 expression (p = 0.024, 0.035 and 0.033, respectively). CONCLUSION: This study demonstrated that PD-L1 expression was associated with MSI-high, increased CD8+ TILs, mucinous and poor cell differentiation, and right-sided tumor location.

Roles and regulation of gastrointestinal eosinophils in immunity and disease.

Eosinophils have historically been considered to be destructive end-stage effector cells that have a role in parasitic infections and allergic reactions by the release of their granule-derived cytotoxic proteins. However, an increasing number of experimental observations indicate that eosinophils also are multifunctional leukocytes involved in diverse inflammatory and physiologic immune responses. Under homeostatic conditions, eosinophils are particularly abundant in the lamina propria of the gastrointestinal tract, where their involvement in various biological processes within the gastrointestinal tract has been posited. In this review, we summarize the molecular steps involved in eosinophil development and describe eosinophil trafficking to the gastrointestinal tract. We synthesize the current findings on the phenotypic and functional properties of gastrointestinal eosinophils and the accumulating evidence that they have a contributory role in gastrointestinal disorders, with a focus on primary eosinophilic gastrointestinal disorders. Finally, we discuss the potential role of eosinophils as modulators of the intestinal immune system.

Development of a novel testis-on-a-chip that demonstrates reciprocal crosstalk between Sertoli and Leydig cells in testicular tissue.

The reciprocal crosstalk between testicular Sertoli and Leydig cells plays a vital role in supporting germ cell development and maintaining testicular characteristics and spermatogenesis. Conventional 2D and the recent 3D assay systems fail to accurately replicate the dynamic interactions between these essential endocrine cells. Furthermore, most in vitro testicular tissue models lack the ability to capture the complex multicellular nature of the testis. To address these limitations, we developed a 3D multicellular testis-on-a-chip platform that effectively demonstrates the reciprocal crosstalk between Sertoli cells and the adjacent Leydig cells while incorporating various human testicular tissue constituent cells and various natural polymers infused with blood coagulation factors. Additionally, we identified SERPINB2 as a biomarker of male reproductive toxicity that is activated in both Sertoli and Leydig cells upon exposure to various toxicants. Leveraging this finding, we designed a fluorescent reporter-conjugated toxic biomarker detection system that enables both an intuitive and quantitative assessment of material toxicity by measuring the converted fluorescence intensity. By integrating this fluorescent reporter system into the Sertoli and Leydig cells within our 3D multicellular chip platform, we successfully developed a testis-on-chip model that can be utilized to evaluate the male reproductive toxicity of potential drug candidates. This innovative approach holds promise for advancing toxicity screening and reproductive research.

Exploring Memory Function Beyond Immune Cells: ANGPTL4-Mediated Memory Functions in Tissue Resident Stem Cells.

Adapted immune cells are known to develop memory functions that increase resistance to subsequent infections after initial pathogen exposure, however, it is unclear whether non-immune cells, like tissue-resident stem cells, have similar memory functions. Here, it is found that tissue-resident stem cells crucial for tissue regeneration show diminished adverse effects on diverse stem cell functions against successive exposure to foreign antigen (ß-glucan) to maintain tissue homeostasis and stability both in vitro and in vivo. These data suggest that endometrial stem cells may possess a robust memory function, in contrast, fully differentiated cells like fibroblasts and vesicular cells do not show these memory mechanisms upon consecutive antigen exposure. Moreover, the pivotal role of Angiopoietin-like 4 (ANGPTL4) in regulating the memory functions of endometrial stem cells is identified through specific shRNA knockdown in vitro and knockout mice in vivo experiments. ANGPTL4 is associated with the alteration of diverse stem cell functions and epigenetic modifications, notably through histone H3 methylation changes and two pathways (i.e., PI3K/Akt and FAK/ERK1/2 signaling) upon consecutive antigen exposure. These findings imply the existence of inherent self-defense mechanisms through which local stem cells can adapt and protect themselves from recurrent antigenic challenges, ultimately mitigating adverse consequences.

GLP-1 and Its Derived Peptides Mediate Pain Relief Through Direct TRPV1 Inhibition Without Affecting Thermoregulation.

Hormonal regulation during food ingestion and its association with pain prompted the investigation of the impact of glucagon-like peptide-1 (GLP-1) on the transient receptor potential vanilloid 1 (TRPV1). Both endogenous and synthetic GLP-1 and an antagonist of GLP-1, exendin 9-39, reduced heat sensitivity in naïve mice. GLP-1-derived peptides (liraglutide, exendin-4, and exendin 9-39) effectively inhibited capsaicin (CAP)-induced currents and calcium responses in cultured sensory neurons and TRPV1-expressing cell lines. Notably, the exendin 9-39 alleviated CAP-induced acute pain, as well as chronic pain induced by complete Freund's adjuvant (CFA) and spared nerve injury (SNI) in mice, without causing hyperthermia associated with other TRPV1 inhibitors. Electrophysiological analyses revealed that exendin 9-39 binds to the extracellular side of TRPV1, functioning as a noncompetitive inhibitor of CAP. Exendin 9-39 did not affect proton-induced TRPV1 activation, suggesting its selective antagonism. Among exendin 9-39 fragments, exendin 20-29 specifically binds to TRPV1, alleviating pain in both acute and chronic pain models without interfering with GLP-1R function. Our study revealed a novel role for GLP-1 and its derivatives in pain relief, proposing exendin 20-29 as a promising therapeutic candidate.

TLR7-dependent eosinophil degranulation links psoriatic skin inflammation to small intestinal inflammatory changes in mice.

Recent evidence of gut microbiota dysbiosis in the context of psoriasis and the increased cooccurrence of inflammatory bowel disease and psoriasis suggest a close relationship between skin and gut immune responses. Using a mouse model of psoriasis induced by the Toll-like receptor (TLR) 7 ligand imiquimod, we found that psoriatic dermatitis was accompanied by inflammatory changes in the small intestine associated with eosinophil degranulation, which impaired intestinal barrier integrity. Inflammatory responses in the skin and small intestine were increased in mice prone to eosinophil degranulation. Caco-2 human intestinal epithelial cells were treated with media containing eosinophil granule proteins and exhibited signs of inflammation and damage. Imiquimod-induced skin and intestinal changes were attenuated in eosinophil-deficient mice, and this attenuation was counteracted by the transfer of eosinophils. Imiquimod levels and the distribution of eosinophils were positively correlated in the intestine. TLR7-deficient mice did not exhibit intestinal eosinophil degranulation but did exhibit attenuated inflammation in the skin and small intestine following imiquimod administration. These results suggest that TLR7-dependent bidirectional skin-to-gut communication occurs in psoriatic inflammation and that inflammatory changes in the intestine can accelerate psoriasis.

A microscale 3D organ on a chip for recapitulating reciprocal neuroendocrine crosstalk between the hypothalamus and the pituitary gland.

Conventional 2D or even recently developed 3Din vitroculture models for hypothalamus and pituitary gland cannot successfully recapitulate reciprocal neuroendocrine communications between these two pivotal neuroendocrine tissues known to play an essential role in controlling the body's endocrine system, survival, and reproduction. In addition, most currentvitroculture models for neuroendocrine tissues fail to properly reflect their complex multicellular structure. In this context, we developed a novel microscale chip platform, termed the 'hypothalamic-pituitary (HP) axis-on-a-chip,' which integrates various cellular components of the hypothalamus and pituitary gland with biomaterials such as collagen and hyaluronic acid. We used non-toxic blood coagulation factors (fibrinogen and thrombin) as natural cross-linking agents to increase the mechanical strength of biomaterials without showing residual toxicity to overcome drawbacks of conventional chemical cross-linking agents. Furthermore, we identified and verified SERPINB2 as a reliable neuroendocrine toxic marker, with its expression significantly increased in both hypothalamus and pituitary gland cells following exposure to various types of toxins. Next, we introduced SERPINB2-fluorescence reporter system into loaded hypothalamic cells and pituitary gland cells within each chamber of the HP axis on a chip, respectively. By incorporating this SERPINB2 detection system into the loaded hypothalamic and pituitary gland cells within our chip platform, Our HP axis-on-chip platform can better mimic reciprocal neuroendocrine crosstalk between the hypothalamus and the pituitary gland in the brain microenvironments with improved efficiency in evaluating neuroendocrine toxicities of certain drug candidates.

SIRPα/CD172a regulates eosinophil homeostasis.

Eosinophils are abundant in the lamina propria of the small intestine, but they rarely show degranulation in situ under steady-state conditions. In this study, using two novel mAbs, we found that intestinal eosinophils constitutively expressed a high level of an inhibitory receptor signal regulatory protein α (SIRPα)/CD172a and a low, but significant, level of a tetraspanin CD63, whose upregulation is closely associated with degranulation. Cross-linking SIRPα/CD172a on the surface of wild-type eosinophils significantly inhibited the release of eosinophil peroxidase induced by the calcium ionophore A23187, whereas this cross-linking effect was not observed in eosinophils isolated from mice expressing a mutated SIRPα/CD172a that lacks most of its cytoplasmic domain (SIRPα Cyto(-/-)). The SIRPα Cyto(-/-) eosinophils showed reduced viability, increased CD63 expression, and increased eosinophil peroxidase release with or without A23187 stimulation in vitro. In addition, SIRPα Cyto(-/-) mice showed increased frequencies of Annexin V-binding eosinophils and free MBP(+)CD63(+) extracellular granules, as well as increased tissue remodeling in the small intestine under steady-state conditions. Mice deficient in CD47, which is a ligand for SIRPα/CD172a, recapitulated these phenomena. Moreover, during Th2-biased inflammation, increased eosinophil cell death and degranulation were obvious in a number of tissues, including the small intestine, in the SIRPα Cyto(-/-) mice compared with wild-type mice. Collectively, our results indicated that SIRPα/CD172a regulates eosinophil homeostasis, probably by interacting with CD47, with substantial effects on eosinophil survival. Thus, SIRPα/CD172a is a potential therapeutic target for eosinophil-associated diseases.

Multifaceted role of CD14 in innate immunity and tissue homeostasis.

CD14 is a co-receptor of Toll-like receptor (TLR)- 4, with a critical role in innate immune responses. CD14 recognizes bacterial lipopolysaccharides, pathogen-, and damage-associated molecular patterns, thereby facilitating inflammatory immune responses. In addition to its well-established association with TLR4, CD14 is also implicated in TLR4-independent signaling, which leads to the apoptotic death of differentiated dendritic cells and activation of the noncanonical inflammasome pathway. CD14 also has a role beyond that of the immune responses. It contributes to tissue homeostasis by promoting the clearance of various apoptotic cells via recognizing externalized phosphatidylinositol phosphates. CD14 also has context-dependent roles, particularly in barrier tissues that include the skin and gastrointestinal tract. For example, CD14+ dendritic cells in the skin can induce immunostimulatory or immunosuppressive responses. In the gastrointestinal system, CD14 is involved in producing inflammatory cytokines in inflammatory bowel disease and maintaining of intestinal integrity. This review focuses on the multifaceted roles of CD14 in innate immunity and its potential regulatory functions in barrier tissues characterized by rapid cell renewal. By providing insights into the diverse functions of CD14, this review offers potential therapeutic implications for this versatile molecule in immune modulation and tissue homeostasis.

MCDAL: Maximum Classifier Discrepancy for Active Learning.

Recent state-of-the-art active learning methods have mostly leveraged generative adversarial networks (GANs) for sample acquisition; however, GAN is usually known to suffer from instability and sensitivity to hyperparameters. In contrast to these methods, in this article, we propose a novel active learning framework that we call Maximum Classifier Discrepancy for Active Learning (MCDAL) that takes the prediction discrepancies between multiple classifiers. In particular, we utilize two auxiliary classification layers that learn tighter decision boundaries by maximizing the discrepancies among them. Intuitively, the discrepancies in the auxiliary classification layers' predictions indicate the uncertainty in the prediction. In this regard, we propose a novel method to leverage the classifier discrepancies for the acquisition function for active learning. We also provide an interpretation of our idea in relation to existing GAN-based active learning methods and domain adaptation frameworks. Moreover, we empirically demonstrate the utility of our approach where the performance of our approach exceeds the state-of-the-art methods on several image classification and semantic segmentation datasets in active learning setups.