1. Mice lacking a gene for syndecan-4 (SDC4), a transmembrane cell receptor, showed less airway inflammation than wild-type (WT) mice in response to ovalbumin (OVA) stimulation.
2. Injecting mice with an antibody targeting SDC4 (anti-SDC4 Ab) mitigated airway inflammation both prophylactically and in an established asthma model.
Evidence Rating Level: 3 (Average) Â Â Â Â
Study Rundown: Asthma, an immune system disorder characterized by airway inflammation and difficulty breathing, affects about 25 million people in the United States alone. Both long- and short-term medications are available for regulating inflammation and other asthmatic symptoms. Researchers here focused on the role of SDC4, which has been shown to play an important role in the immune response, as a potential novel target in asthma treatment.
Initial results showed that mice lacking the SDC4 gene (SDC4-/- mice) exhibited less inflammation than WT mice in response to OVA, which stimulates an asthma-like allergic reaction. Lower inflammation in SDC4-/- mice was evident in lung histology as well as lower white blood cell counts, airway hyperresponsiveness, and inflammation marker levels in the mediastinal lymph nodes. Administering normal mice with anti-SDC4 Ab prior to OVA injection had similar effects. In another mouse model, mice were first stimulated with OVA to yield an established asthma phenotype, and then treated with anti-SDC4 Ab prior to subsequent OVA challenge. These mice similarly showed decreased inflammation and airway hyperresponsiveness as compared to controls. Subsequent experiments focused on the mechanism of SDC4 involvement in airway inflammation, with results suggesting that SDC4 is important in the motility of inflammatory cells.
This study identifies SDC4 as a potential new target for asthma treatment. Since SDC4 is ubiquitously expressed in the human body, the biggest challenge with developing an SDC4 inhibitor for clinical use is precisely targeting it to specific cells during inappropriate airway inflammation. Additionally, the benefit of such an inhibitor over existing asthma medications must be demonstrated.
Click to read the study in Nature Communications
In-Depth [animal study]: To model asthmatic inflammation, SDC4-/- and WT mice were immunized intraperitoneally with OVA on days 1 and 14, then challenged intranasally with OVA on days 14-16 and 21-23. SDC4-/- mice showed decreased airway inflammation in response to OVA as compared to WT mice (p<0.05; n≥9 per group for all animal experiments), as quantified by software that analyzed lung histology samples. OVA increased several inflammatory markers in WT mice, including the number of eosinophils in the bronchoalveolar fluid, OVA-specific IgE levels, and mediastinal lymph node levels of interleukins 5 and 13. All of these effects were mitigated in SDC4-/- mice (p<0.05). Airway hyperresponsiveness, measured as the lung resistance to inhaled methacholine, showed a lesser increase in OVA-exposed SDC4-/- mice than WT mice (p<0.05 for 20, 40 or 80 mg/ml methacholine).
Anti-SDC4 Ab was tested as a prophylactic therapy and a treatment for established asthma. Normal mice treated prophylactically on days 0 and 13 with anti-SDC4 Ab showed significantly reduced inflammation upon OVA challenge compared to mice treated with control antibody, using the same metrics as the SDC4-/- mice experiments. In an established asthma mouse model as described above (with day 14 OVA immunization omitted), anti-SDC4 Ab was administered on days 18 and 22. Inflammation measures in these mice were significantly lower than those in mice treated with control antibody.
Final experiments focused on the mechanisms behind SDC4 involvement in airway inflammation. Dendritic cells (DCs) from SDC4-/- mice displayed decreased migration when compared with WT DCs (p<0.05), which, coupled with other findings, suggested that SDC4 is involved in DC migration and resulting ability to stimulate the immune response.
Image: PD
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