The drivers of TH2 inflammation in the chronic phase of disease is currently not as well understood as those in the initiation phase. Yet the effector functions of leukocytes in the chronic phase of TH2 inflammation drive symptomatic human disease that often results in irreversible immune pathology associated with tissue remodeling, fibrosis, and much morbidity. This is well characterized in chronic allergic diseases such as asthma and atopic dermatitis. Chemokines are chemotactic cytokines that control leukocyte recruitment and inflammation by binding specific receptors on target cells. We recently discovered a new chemokine ligand mouse CCL8 (mCCL8) for the chemokine receptor CCR8 which is expressed by TH2 cells that are central to the TH2 inflammatory response. Functional CCR8 expression is restricted to antigen-experienced TH2 cells. We found that the CCR8-mCCL8 pathway drives chronic eosinophilic inflammation in a model of chronic atopic dermatitis. mCCL8 is the most highly induced chemokine in inflamed atopic skin, and is also highly induced in alternatively activated macrophages (AAMs) differentiated in the presence of IL-4. The human chemokine CCL18 is a specific marker of human AAMs, and is correlated with disease severity in several chronic human diseases including atopic dermatitis. Investigations into how CCL18 promotes inflammation have been impeded by the fact that CCL18 lacks an identified chemokine receptor and a rodent ortholog. We have discovered that CCL18 is a second ligand for the human CCR8 receptor. Studies also suggest that mCCL8 and CCL18 are regulated by similar inflammatory cues, leading us to hypothesize that they are functional orthologs, and both amplify inflammation in the chronic phase of disease through the effector functions of AAMs and memory TH2 cells. To test this hypothesis we propose to: (1) Define the inflammatory regulators of mCCL8 and CCL18 induction;(2) Define how mCCL8 and CCL18 induction is transcriptionally regulated in response to IL-4 signaling;(3) Define the in vivo contribution of AAMs and the CCR8 pathway to chronic TH2 inflammation in the model of chronic atopic dermatitis;(4) Determine the role of the CCR8 pathway in the generation and maintenance of CD4 TH2 memory responses in chronic cutaneous TH2 inflammation. The first two aims will establish that mCCL8 and CCL18 are functional analogs.
This research will further facilitate the use of the CCR8 receptor-ligand pathway in rodent models to investigate mechanisms by which CCL18 promotes chronic human disease;will also provide new mechanistic insights into chronic TH2 inflammation, in particular, the pathogenesis of eczema which is a cause of great morbidity in children and often presages the development of asthma in later life. PUBLIC HEALTH RELEVANCE: Dysregulated chronic TH2-type inflammation drives several chronic human diseases, some of which currently have limited therapeutic options. Pathogenic chronic TH2-type inflammation is evident in atopic diseases such as asthma and atopic dermatitis, fibrotic disorders such as pulmonary fibrosis, and has been seen in tumors such as ovarian and breast cancer in the setting of TH2-type inflammatory responses. This application proposes to understand mechanisms by which TH2 cells and alternatively activated macrophages use the CCR8 chemokine receptor and its chemokine ligands to amplify disease in the chronic phase of TH2 inflammation. Doing so will aid in developing new targeted therapies.