Human airway epithelial cells express ABCC4/MRP4, a transporter for uric acid and cAMP secretion, that contributes to innate and adaptive immune responses. — ASN Events
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  3. Human airway epithelial cells express ABCC4/MRP4, a transporter for uric acid and cAMP secretion, that contributes to innate and adaptive immune responses.

Human airway epithelial cells express ABCC4/MRP4, a transporter for uric acid and cAMP secretion, that contributes to innate and adaptive immune responses. (#265)

Jeremy A Hirota 1 , Matt Gold , Paul Hiebert , HyeYun Park , Dorota Stefanowicz , Kelly McNagny , Darryl Knight , Don Sin , Chris Carlsten
  1. University of British Columbia, Vancouver, BC, Canada

HYPOTHESIS:  Uric acid can be detected in airway lining fluids, although the mechanism regulating this process remains unclear.  Uric acid is a potent anti-oxidant at physiological concentrations while becoming a danger associated molecular pattern triggering innate immune responses at pathological concentrations.  Extracellular cAMP has also been shown to modulate immune responses.  We tested the hypothesis that human airway epithelium expresses ABCC4/MRP4 which can regulate uric acid and cAMP secretion contributing to context dependent airway health and pathology.

METHODS:  We used in vitro experiments with human airway epithelial cells and in vivo mouse models of airway disease.  We performed candidate uric acid transporter gene expression, in situ immunohistochemistry, and in vitro pharmacological intervention experiments with human airway epithelial cells.  We assessed the functional consequences of this system in a mouse model of allergic airways disease.

RESULTS: We demonstrate gene and protein expression of ABCC4/MRP4 in human airway epithelial cells in vitro and in situ.  In vitro airway epithelial cells secrete basal levels of uric acid further induced with allergen treatment.  ABCC4/MRP4 inhibition significantly blocked basal and induced uric acid secretion, without changes in cell death. This data suggests a uric acid transport system is active and does not require cell death.  Inhibition of ABCC4/MRP4 also attenuated forskolin induced cAMP secretion.  In vivo intervention studies targeting uric acid at the mucosal surface prevented allergic sensitization in a model of air pollution and allergen co-exposure.  

CONCLUSIONS:  Our results are the first to demonstrate the presence and function of a uric acid and cAMP transport system in human airway epithelial cells.  Our results open the door to begin exploring how this transport system is regulated in health and disease, the downstream consequences of activation of the system, and the potential for the system to be active at other mucosal surfaces throughout the body.

Research Funding Source: Canadian Institutes of Health Research.  BC Lung Association.  Canadian Banting Fellowship Program