Bone Morphogenetic Proteins Modulate Mast Cell Responses During Inflammation

Chronic inflammatory conditions can lead to detrimental health conditions that become difficult to manage and treat. Ultimately treatment requires modulation of the critical cell types involved in pathology in order to achieve homeostasis. Mast cells, a type of innate immune cell located at areas of high antigen load, are commonly thought of as primarily pro-inflammatory, but are becoming increasingly recognized in other roles, such as wound healing, anti-inflammatory actions, and homeostatic functions. In this study we investigate the role of mast cell subtypes and inflammatory mechanisms via in vitro assays using mouse and human mast cells, as well as relate to a clinical disease that involves mast cells, equine asthma.

The first part of the dissertation reviews literature regarding mast cell’s presence in two chronic inflammatory conditions, asthma and inflammatory bowel disease (IBD). Additionally, I present a potential protective axis in inflammation, mast cell - bone morphogenetic protein (BMP),that was initially discovered in our laboratory in a mouse model of colitis.

In the second part we evaluated the mast cell – BMP axis in relation to modulating mast cell functions. We observed that mast cells produce BMPs in an inflammatory environment and these BMPs are able to modulate mast cell functions in an anti-inflammatory manner. Additionally, BMP signaling in mast cells has the potential to be both anti- and pro-inflammatory depending on the BMP receptor engaged.

In the third part we investigated the mast cell molecular phenotype found in equine asthma in relation to the inflammatory cytokine/chemokine milieu, in addition to anti-inflammatory and pro-fibrotic factors. We observed that horses with mastocytic asthma have different mast cell phenotypes from healthy or other asthma subtypes. Additionally, there is potential dysregulation of BMPs in severe asthma.

Collectively, these studies identified a potential important role for BMPs and their signaling in mast cell functions and regulating inflammation. Increasing the knowledge of the mast cell – BMP axis may be important in multiple chronic inflammatory conditions, such as asthma and IBD, and be a target for therapy.