The semaphorin family of membrane proteins was initially characterized as axon-guidance molecules criti- cal for neuronal development. It is now recognized that they play critical roles in a number of physiological and pathologic responses including angiogenesis, cancer, and inflammation by binding to a diverse array of counter receptors. Recent studies suggest that semaphorins can act as co-stimulatory molecules. Se- ma4A was previously shown to be an important co-stimulatory molecule for T-cell activation in vitro and for Th1-inflammation in vivo. Sema4A was shown to control the Th1/Th2 balance. However, we recently demonstrated that Sema4A played a down-regulatory role during allergic (Type II) inflammation in vivo. We observed increased allergic airway inflammation accompanied by increased IL-13 and lower Treg numbers in allergen-treated Sema4A-/- mice compared to WT mice. Interestingly, allergic inflammation was significantly reduced in either WT or Sema4A-/- mice by administration of recombinant soluble Se- ma4A. Based on these results, we propose that Sema4A is a negative regulator of Th2-driven responses. However, the mechanism by which Sema4A dampens allergic inflammation is unknown, representing a significant gap in knowledge. Thus, the overall goal of this research proposal is to determine the mecha- nism by which Sema4A limits allergic inflammation. Based on our preliminary data, we hypothesize that Sema4A limits allergic inflammation through interaction with Plexin-B1 to enhance the numbers and activi- ty of Tregs. This hypothesis will be tested by completing the following specific aims: 1) to characterize the contribution of Sema4A / Plexin B1 interaction in the control of T cell responses in allergic lung inflamma- tion, 2) to evaluate the contribution of Plexin B1 to the suppressive activity of Sema4A in vivo, and 3) to delineate the critical amino acids responsible for Sema4A interaction with Plexin B1. Our research has significant potential to identify novel therapeutic strategies to treat allergic inflammation.
This research project will analyze how the cell surface protein Semaphorin 4A suppresses the inflammatory response induced by inhaled allergens. This process is important to understand because allergic inflammation can initiate and amplify the symptoms of asthma. Our proposed studies may identify new targets for the treatment of asthma.
