CD44 is critical for the enhancing effect of hyaluronan in allergen-specific sublingual immunotherapy in a murine model of chronic asthma.
Clinical and experimental immunology
Allergen-specific sublingual immunotherapy (SLIT) is a potentially effective disease-modification treatment for patients with allergic asthma. Because CD44 signaling enhances regulatory T (Treg) cell-induction, administering CD44 ligands such as hyaluronan (HA) with allergen-specific SLIT may enhance the therapeutic effects. We evaluated the role of CD44 in Treg cell-induction in T helper type 2 (Th2)-mediated chronic airway inflammation using CD44-/- mice and the efficacy of HA on SLIT in a Dermatophagoides farinae (Df)-induced murine model of chronic asthma. Th2 responses and Treg cell induction were evaluated in CD44-/- mice. We devised a new SLIT model of Df-induced chronic asthma utilizing HA as an adjuvant. The effects of HA added to the new SLIT model were evaluated by the early asthmatic response (EAR) and airway hyperresponsiveness (AHR), eosinophilic airway inflammation, and serum Df-specific IgE levels. Th2-mediated chronic eosinophilic airway inflammation was worse in CD44-/- mice compared with Df-sensitized wild-type (WT) mice. HA enhanced the effect of Df-induced Treg cells in a CD44-dependent manner. Sublingual Df treatment in combination with HA, but not alone, normalized EAR and AHR, and significantly reduced the serum IgE levels and the bronchoalveolar lavage fluid (BALF) eosinophil number. HA also induced Treg cells in a Df-sensitized spleen cell culture in a CD44-dependent manner. The treatment-enhancing effects of HA in this SLIT model were diminished in CD44-/- mice. CD44 is a key contributor to Treg cell induction and critical for the enhancing effects of HA in a Df-induced murine model of chronic asthma.
CD44 Promotes Inflammation and Extracellular Matrix Production During Arteriovenous Fistula Maturation.
Kuwahara Go,Hashimoto Takuya,Tsuneki Masayuki,Yamamoto Kota,Assi Roland,Foster Trenton R,Hanisch Jesse J,Bai Hualong,Hu Haidi,Protack Clinton D,Hall Michael R,Schardt John S,Jay Steven M,Madri Joseph A,Kodama Shohta,Dardik Alan
Arteriosclerosis, thrombosis, and vascular biology
OBJECTIVE:Arteriovenous fistulae (AVF) remain the optimal conduit for hemodialysis access but continue to demonstrate poor patency and poor rates of maturation. We hypothesized that CD44, a widely expressed cellular adhesion molecule that serves as a major receptor for extracellular matrix components, promotes wall thickening and extracellular matrix deposition during AVF maturation. APPROACH AND RESULTS:AVF were created via needle puncture in wild-type C57BL/6J and CD44 knockout mice. CD44 mRNA and protein expression was increased in wild-type AVF. CD44 knockout mice showed no increase in AVF wall thickness (8.9 versus 26.8 μm; =0.0114), collagen density, and hyaluronic acid density, but similar elastin density when compared with control AVF. CD44 knockout mice also showed no increase in vascular cell adhesion molecule-1 expression, intercellular adhesion molecule-1 expression, and monocyte chemoattractant protein-1 expression in the AVF compared with controls; there were also no increased M2 macrophage markers (transglutaminase-2: 81.5-fold, =0.0015; interleukin-10: 7.6-fold, =0.0450) in CD44 knockout mice. Delivery of monocyte chemoattractant protein-1 to CD44 knockout mice rescued the phenotype with thicker AVF walls (27.2 versus 14.7 μm; =0.0306), increased collagen density (2.4-fold; =0.0432), and increased number of M2 macrophages (2.1-fold; =0.0335). CONCLUSIONS:CD44 promotes accumulation of M2 macrophages, extracellular matrix deposition, and wall thickening during AVF maturation. These data show the association of M2 macrophages with wall thickening during AVF maturation and suggest that enhancing CD44 activity may be a strategy to increase AVF maturation.
Critical Involvement of CD44 in T Helper Type 2 Cell-Mediated Eosinophilic Airway Inflammation in a Mouse Model of Acute Asthma.
Frontiers in immunology
Interactions between CD44 and hyaluronan (HA) are crucial for recruiting leukocytes to inflamed tissues. This review summarizes findings from our studies of the roles of CD44-HA interactions in leukocyte trafficking, with a particular focus on airway T helper type 2 (Th2) cells in mouse models of acute asthma. In a mite allergen-induced model of acute asthma, intraperitoneal injection of anti-CD44 monoclonal antibodies blocked lymphocytes and eosinophils from accumulating in the lung, and suppressed both the antigen-induced increase in Th2 cytokines in the bronchoalveolar lavage fluid (BALF) and airway hyperresponsiveness (AHR). CD44 deficiency was associated with decreased mite allergen-induced Th2 cell-mediated airway inflammation and AHR in sensitized mice. Asthmatic responses to antigen-sensitized splenic CD4 T cells transferred from CD44-deficient mice were weaker than in wild-type mice. Administration of anti-CD44 monoclonal antibodies preferentially suppressed the airway accumulation of antigen-specific Th2 cells induced by antigen challenge, without affecting Th1 and Th17 cells. Increased HA-binding ability of CD44 and expression of Neu1 sialidase were observed on antigen-specific Th2 cells compared with antigen-specific Th1 and Th17 cells. Finally, in a mouse model of acute asthma, neuraminidase 1-deficient SM/J mice exhibited a lower Th2 cytokine concentration and a lower absolute Th2 cell number in the BALF, as well as an attenuated AHR. Our findings indicate that CD44 critically contributes to the antigen challenge-induced airway accumulation of antigen-specific Th2 cells, without affecting Th1 and Th17 cells, in mice. Furthermore, neuraminidase 1 activity is necessary for the interaction between HA and CD44, and Th2 cell-mediated airway inflammation.
CD44 Glycosylation as a Therapeutic Target in Oncology.
Frontiers in oncology
The interaction of non-kinase transmembrane glycoprotein CD44 with ligands including hyaluronic acid (HA) is closely related to the occurrence and development of tumors. Changes in CD44 glycosylation can regulate its binding to HA, Siglec-15, fibronectin, TM4SF5, PRG4, FGF2, collagen and podoplanin and activate or inhibit c-Src/STAT3/Twist1/Bmi1, PI3K/AKT/mTOR, ERK/NF-κB/NANOG and other signaling pathways, thereby having a profound impact on the tumor microenvironment and tumor cell fate. However, the glycosylation of CD44 is complex and largely unknown, and the current understanding of how CD44 glycosylation affects tumors is limited. These issues must be addressed before targeted CD44 glycosylation can be applied to treat human cancers.
Ligation of Siglec-8: a selective mechanism for induction of human eosinophil apoptosis.
Nutku Esra,Aizawa Hideyuki,Hudson Sherry A,Bochner Bruce S
Sialic acid binding immunoglobulin-like lectin 8 (Siglec-8), which exists in 2 isoforms including one possessing cytoplasmic tyrosine motifs, is expressed only on human eosinophils, basophils, and mast cells. Until now, its function was unknown. Here we define a novel function of Siglec-8 on eosinophils. Siglec-8 cross-linking with antibodies rapidly generated caspase-3-like activity and reduced eosinophil viability through induction of apoptosis. The pancaspase inhibitor benzyloxycarbonyl (Cbz)-Val-Ala-Asp-(Ome)-fluoromethyl ketone (zVAD-FMK) completely blocked this response, implicating caspases in Siglec-8 cross-linking-induced apoptosis. Eosinophil survival-promoting cytokines such as interleukin 5 (IL-5) and granulocyte-macrophage colony-stimulating factor (GM-CSF) failed to block apoptosis and instead enhanced the sensitivity of eosinophils to undergo apoptosis in response to Siglec-8 antibody. Siglec-8 activation may provide a useful therapeutic approach to reduce numbers of eosinophils (and perhaps basophils and mast cells) in disease states where these cells are important.
Diagnostic and Predictive Values of Ferroptosis-Related Genes in Child Sepsis.
Frontiers in immunology
Background:Early diagnosis of sepsis in children was essential to reducing mortality. This study aimed to explore the value of ferroptosis-related genes in children with sepsis. Methods:We screened the septic children microarray dataset from the GEO database and analyzed the ferroptosis-related differentially expressed genes (DEGs). A functional analysis of ferroptosis-related DEGs was performed. The protein-protein interaction network was used to identify hub genes. We explored the immune landscape of sepsis and controls. The value of hub genes in diagnosing sepsis was tested in the training (GSE26440) and validation sets (GSE13904), and ELISA was used to verify their diagnostic value in children with sepsis in our hospital. Results:A total of 2,103 DEGs in GSE26440 were obtained, of which ferroptosis-related DEGs were 34. Enrichment analysis showed significant enrichment in the ferroptosis and hypoxia pathways (i.e., HIF-1 pathway). The top three genes (HMOX1, MAPK14, TLR4) were selected as hub genes. Immunological analysis suggested that 10 cell types (i.e., CD8/CD4 T cells) were lower in sepsis. Immune checkpoint-related genes CD274 (PD-L1), HAVCR2 (TIM3), and SIGLEC15 were overexpressed in sepsis. The AUROC for the diagnosis of sepsis for HMOX1 and TLR4 ranged from 0.77 to 0.81, while the AUROC of MAPK14 reached 0.935 and 0.941 in the training and validation sets. Serum ELISA results of HMOX1 and TLR4 showed no significant difference in differentiating sepsis. The AUROC of MAPK14 was 0.877. When the diagnostic threshold was 74.852 ng/ml, the sensitivity and specificity were 0.906 and 0.719, respectively. Conclusion:Ferroptosis-related gene MAPK14 is of considerable value in the early diagnosis of sepsis in children.