Complement C3a regulates Muc5ac expression by airway Clara cells independently of Th2 responses

The factors that control the secretion of epithelial mucins are essential to understanding obstructive airway diseases such as asthma. Although the complement anaphylatoxin C3a and its receptor have been shown to promote many features of allergic lung inflammation, the contribution to mucin expression has not been elucidated.

To determine if the C3a receptor with its ligand regulates airway epithelial mucin production.

Mice deficient in the C3a receptor were examined in a model of allergic airway disease for the presence of goblet cells and the gel-forming secreted mucin Muc5ac.

Lungs from antigen-challenged C3a receptor-deficient mice revealed a dramatic decrease in goblet cells and Muc5ac compared with challenged wild-type control animals. These differences were dependent on C3a binding to its receptor since intranasal challenge with C3a induced the formation of goblet cells only in wild-type but not C3a receptor-deficient mice. Increased numbers of goblet cells were also found in C3a-stimulated RAG-1-deficient mice demonstrating a mechanism independent of T lymphocytes and Th2 cytokines, mediators which have been shown to regulate mucin expression. A direct physiological role for C3a in these models was further demonstrated in cultures of airway epithelial Clara cells, which not only express the C3a receptor but also produce Muc5ac in response to C3a.

These studies identify a novel C3a receptor-dependent mechanism in the development of airway epithelial goblet cells and regulation of Muc5ac production and implicate C3a as a mediator of airway obstruction in asthma.