The Role of Cdc42 in Regulating the Production and Release of Pro-inflammatory Cytokines in Airway Epithelial Cells.

More than 3.8 million Canadians are living with asthma. Chronic lung inflammatory diseases such as asthma and COPD (chronic obstructive pulmonary disease) are characterized by secretion of harmful proteins that trigger destructive inflammation. These proteins, known as cytokines, are the body's natural alarms that notify the immune system against the presence of pathogens and toxins. However, excessive secretion of these proteins, especially in response to harmless allergens, can be detrimental in the lung milieu as it can cause extensive tissue damage to the airways in chronic inflammation. This process is also particularly pivotal in viral infections such as in COVID-19, where the 'cytokine storm' is conducive to multi-organ failure and even death. Although these proteins can be secreted by a variety of different cell types in the body, the epithelial cells that line the pulmonary tracts are particularly important secretors of these cytokines. This is because these cells are regularly the first cells to come into contact with external triggers and initiate an inflammatory response. In fact, the secretion of cytokines by epithelial cells is known to drive downstream inflammation by recruiting and activating immune cells. This ultimately results in the instigation of a robust (and threatening) pro-inflammatory reaction. Currently, the signalling and trafficking pathways that control the release of cytokines from epithelial cells are vaguely illustrated. In our project, we propose a group of signalling proteins, known as Rho GTPases, as underlying regulators of this process of cytokine release. These proteins are known to transduce external signals into cues for gene expression and secretion. However, their role in pro-inflammatory cytokine production and secretion within lung epithelial cells remains unknown. We use cellular models of asthma and viral infections to mimic inflammation and characterize the specific contributions of Rho proteins within these processes.