The purposes of the project are to investigate the biological roles of members of the chemokine family of cytokines, to use chemokine receptors to understand the relationships between the trafficking patterns and broader biological functions of subsets of effector/memory T cells, and to understand the contributions of the chemokine system to infectious and inflammatory/autoimmune disease and cancer. Chemokines and their receptors are critical for leukocyte trafficking, and our experiments are directed to understanding how manipulating the chemokine system could be used to treat diseases in which leukocytes play a critical role. In addition, some chemokine receptors are expressed by cancer cells, and these receptors can potentially be exploited for diagnosis and as targets for therapy. In FY 2013, we have continued to investigate a mouse model of skin inflammation that has features of psoriasis. The model involves injection of a cytokine, IL-23, which appears to have a role not only in psoriasis, but also in other immune-mediated diseases, such as Crohns disease. We and others had described that the chemokine receptor CCR6 is expressed by IL-23-dependent T cells that produce the cytokines IL-17 and IL-22. IL-22 and IL-17 are important in producing disease in the mouse psoriasis model, and are thought to be important in causing tissue injury in some autoimmune diseases. We have shown previously that mice lacking CCR6 are resistant to the IL-23-induced disease, but the mechanism has been unclear. In the past year, using bone marrow transplantation, we have shown that the activity of CCR6 in this model is confined to the hematopoietic cells. In order to understand better the activities of CCR6 on leukocyte subsets, we have characterized the types of monocyte/macrophage and dendritic cell subsets that infiltrate the skin and contribute to the psoriasis-like inflammation. Monocyte/macrophages and dendritic cells are cells of the innate immune system that produce pro-inflammatory factors and affect the activities of other immune cells, such as T cells. We have identified a subset of inflammatory dendritic cells that enter the outer layers of the skin (epidermis) during the inflammatory response. We have also identified a number of factors secreted by dendritic cells and/or macrophages that contribute to the skin disease. A second part of the project in the last year has involved using CCR6 expressed on helper T cells from human blood to study the mechanisms controlling gene expression that allow these cells to produce the factors, such as IL-17 and IL-22, that contribute to autoimmune/inflammatory disease. We have identified a number of proteins that regulate the expression of the genes for CCR6, IL-17 and other proteins important for the activities of Th-17-cells. These regulatory proteins affect both the ability of nave T cells to become Th17 cells and the ability of Th17 cells to maintain their activities. A third part of the project has focused on the process whereby effector/memory T cells migrate from the blood, across the layer of endothelial cells that line the inside of the blood vessel, into a site of tissue infection or inflammation. In the last year we have characterized subsets of CD8+ (killer) T cells that are particularly efficient at migrating across the endothelium, and we have identified some of the molecular features of the surfaces of these cells, including the combination of chemokine receptors, that make them so efficient. A fourth part of the project has focused on functions for CXCR4 and its ligand, CXCL12, in the physiology and adenomas of the adrenal gland. CXCR4 is an unusual chemokine receptor, in that it has roles outside of the hematopoietic system, including in the development of the nervous and cardiovascular systems and the positioning of germ cells. We found that CXCR4 is highly expressed on zona glomerulosa cells, in both mouse and human. In mouse adrenal cortex, CXCL12 mRNA and protein, respectively, are expressed near the adrenal capsule, correlating with the site of CXCR4 expression. We have also found high levels of CXCR4 expression in aldosterone-producing adenomas and hyperplasias.
|Xu, Xin; Weiss, Ido D; Zhang, Hongwei H et al. (2014) Conventional NK cells can produce IL-22 and promote host defense in Klebsiella pneumoniae pneumonia. J Immunol 192:1778-86|
|Bachelerie, Francoise; Ben-Baruch, Adit; Burkhardt, Amanda M et al. (2014) International Union of Basic and Clinical Pharmacology. [corrected]. LXXXIX. Update on the extended family of chemokine receptors and introducing a new nomenclature for atypical chemokine receptors. Pharmacol Rev 66:1-79|
|Mabuchi, Tomotaka; Singh, Tej Pratap; Takekoshi, Tomonori et al. (2013) CCR6 is required for epidermal trafficking of ??-T cells in an IL-23-induced model of psoriasiform dermatitis. J Invest Dermatol 133:164-71|
|Auerbach, Michael B; Shimoda, Naohiko; Amano, Hiroyuki et al. (2009) Monokine induced by interferon-gamma (MIG/CXCL9) is derived from both donor and recipient sources during rejection of class II major histocompatibility complex disparate skin allografts. Am J Pathol 174:2172-81|
|Hedrick, Michael N; Lonsdorf, Anke S; Shirakawa, Aiko-Konno et al. (2009) CCR6 is required for IL-23-induced psoriasis-like inflammation in mice. J Clin Invest 119:2317-29|
|Muse, Michael; Kane, Joy A C; Carr, Daniel J J et al. (2008) Insertion of the CXC chemokine ligand 9 (CXCL9) into the mouse hepatitis virus genome results in protection from viral-induced encephalitis and hepatitis. Virology 382:132-44|