Cytokines and host defence peptides: Mechanisms of immunomodulation

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Inflammation is a fundamental element of efficient immunity. However, this biological process must be self-limiting or regulated to maintain a healthy state (immune homeostasis). Molecules known as cytokines orchestrate immune responses and mediate inflammation when required. Cytokine-mediated inflammation is meticulously regulated / controlled by different cellular mechanisms to maintain immune homeostasis. Studies in the last three decades indicate that endogenous molecules known as cationic host defence peptides (CHDP) are important in the regulation of inflammation. CHDP have a wide range of immunity-related functions and contribute to immune homeostasis. CHDP can mediate both pro- and anti-inflammatory responses depending on the cellular environment, and selectively regulate the inflammatory process. Cathelicidins and Defensins are the two best characterized groups of CHDP in mammals. The effect of CHDP on cytokine-mediated cellular responses at mucosal surfaces (i.e. areas that line body cavities and cover the surface of internal organs) remains to be fully elucidated. Gap in knowledge: CHDP can modulate cytokine mediated-inflammation, but the underlying mechanisms by which this occurs (i.e. protein changes and cell signaling) are not completely understood. Moreover, how cytokines may change CHDP expression remains undefined.  The long term vision of my NSERC DG program is to define mechanisms by which CHDP modulate cytokine-induced responses, to regulate inflammation and maintain immune homeostasis. My DG research will add to the understanding of the fundamental biology in the interplay of CHDP and cytokines. Short term objectives: Recently, I have shown that CHDP cathelicidin LL-37 selectively regulates cytokine-mediated inflammation in blood-derived cells and in epithelial cells (structural cells that make up tissues). My 5-yr short term objectives are to examine how LL-37 alters cellular responses and signaling mechanisms in the presence of two cytokines (IL-17 and IFN-gamma) using two different cell types. I also aim to define molecular processes that control the pro- vs anti-inflammatory responses mediated by LL-37. The long term goal is to expand my research scope to include other CHDP such as ß-defensins, and to comprehensively understand how CHDP alter cytokine-induced inflammation. I have recently shown that some cytokines can change the expression profile of certain CHDP. Thus, a further long term goal will be to focus on the feedback loop (interplay) between cytokines and CHDP that allows them to control one another's abundance in different cell types. Impact: My program will define the receptors, protein targets and pathways in the immunomodulatory functions of CHDP. This will facilitate detailed investigation of the dynamic processes in maintaining inflammatory homeostasis. My lab provides training in an interdisciplinary environment, including Immunology & Systems Biology, rapidly growing areas of life sciences.