As effective regulators of extravasation, chemokines shape the inflammatory process significantly through preferential cell targeting. That multiple chemokines are present at sites of inflammation suggests they interact to control target cell recruitment. Yet, the impact of simultaneous chemokine production on the composition, magnitude, and kinetics of inflammatory responses has largely been ignored. We hypothesize that cooperative chemokine interactions contribute to the orchestration of inflammation by controlling cellular recruitment dynamics. Multiple chemokines, including CXCL9 and CXCL10, are expressed in islet tissue of mice with type 1 diabetes suggesting an important role for chemokine multiplicity in autoimmunity. Preliminary studies demonstrate synergism exists between CXCL9 and CXCL10. Since both chemokines are highly homologous, bind identical receptors, and are capable of cross-desensitization, the observed synergism is surprising. The current proposal extends this observation to address several unresolved questions central to unraveling how chemokines work together to shape inflammation.
The specific aims are: 1) to quantitate the specificity, magnitude, and kinetics of cellular recruitment by CXCL9 and CXCL10 individually in vivo, 2) to elucidate the impact of chemokine synergism on cell migration and inflammation, and 3) to model select CXCL9 and CXCL10 expression patterns in vivo. Quantitative approaches (fluorescence microscopy and flow cytometry) will be taken to delineate the parameters of CXCL9 and CXCL10 function individually and in combination in vivo using chemokine-expressing transfectants as cellular chemokine sources. Tissue specific effects will be addressed by exploring chemokine-mediated functions at two distinct sites: subcutaneous interstitium and peritoneum. A complementary model system using osmotic infusion pumps will be developed to test the in vivo effects of various chemokine expression patterns on cell recruitment. Information gained through the proposed studies will provide novel insights into the mechanisms controlling the dynamic process known as inflammation. Through increased understanding of these mechanisms, new therapeutic approaches may be conceived to control or treat pathologic inflammation such as occurs in autoimmune disorders.
| Pabbidi, Reddy M; Yu, Shuang-Quan; Peng, Siying et al. (2008) Influence of TRPV1 on diabetes-induced alterations in thermal pain sensitivity. Mol Pain 4:9 |
