The RNA-binding Protein KSRP inhibits allergic reactions by dampening Th2 responses
PALZER K. 1, BOLDUAN V. 1, LAKUS J. 1, BROS M. 1, PAUTZ A. 1
1 University Medical Center Mainz, Mainz, Germany
Objectives: Chronic inflammatory diseases are characterized by dysregulated immune responses and increased expression of pro-inflammatory genes. Asthma is a chronic inflammatory disease, which is characterized by allergic airway inflammation, IgE- and Th2-cytokine production as well as increased eosinophil infiltration in the respiratory tract and results in airway hyperresponsiveness (AHR). The conventional treatment of asthma primarily targets the symptoms but not the cause of disease. To identify new drug targets the characterization of pathways that resolve inflammation is necessary. The RNA-binding protein KH-type splicing regulatory protein (KSRP) controls the mRNA stability of immune relevant genes for example by initiation of mRNA decay. As KSRP plays a pivotal role in innate and adaptive immune cell function, we were interested whether knockdown of the protein (KSRP-/-) affects the outcome of allergic asthma.
Methods: To investigate the role of KSRP in allergic asthma we studied the immunomodulatory effect of KSRP in an in vivo ovalbumin-(OVA)-asthma mouse-model which is characterized by a Th2-biased immune response. We compared asthma induction in wild type and KSRP-/- mice. Lungs were taken for histological sections as well as cytokine levels in lung tissue and bronchial lavage supernatant (BAL) were determined by qRT-PCR and cytometric bead array analyses.
Results: We found that KSRP-/- mice sensitized with OVA appear to have a higher AHR and increased eosinophil infiltration in the lung. In accordance, Th2-associated cytokine levels were enhanced in lung tissue and BAL supernatants of OVA treated KSRP-/- mice. These results fit to the increased number of immune cells around the bronchi and alveoli, the higher number of mucus producing goblet cells and the increased production of OVA-specific IgE and IgG1 in serum of OVA treated KSRP-/- mice.
Conclusion: To sum up, we have strong evidence that allergic asthma is aggravated in KSRP-/- mice by promotion of a Th2-based immune response.