Regulation of neutrophil plasticity, heterogenicity, and functional ambivalency by WNT5 in colitis

Project Summary / Abstract: Neutrophils are the most abundant leukocytes in the circulation. They are the first to be recruited to the sites of inflammation and abundantly present in many inflammatory diseases. Neutrophils are important for host defense against microbial infections, but also responsible for tissue injuries during acute and chronic inflammation responses. Thus, they are generally considered as being detrimental to tissue well-being in sterile inflammation-related diseases such as acute lung injury and myocardial, renal, and cerebral ischemia-reperfusion injuries as well as some of the autoimmune diseases (inflammatory bowel disease and Type I diabetes). Neutrophils possess great plasticity, heterogenicity, and functional ambivalency. They can be beneficial or detrimental to host well-being depending on contexts. In our investigation of WNT5A and WNT5B, we found that the lack of these proteins protected colitis as the result of increased suppression of colon cytotoxic CD8 T cells by CD101-high neutrophils. These CD101 high neutrophils are produced from splenic extramedullar hematopoiesis, which is stimulated by WNT5-deficiency. In this application, we plan to examine the role of CD101 in immune suppression, characterize functional responses of CD101-high neutrophils, investigate the mechanisms for WNT5 to regulate splenic EMH, and determine the transcription factors that control molecular and hyper-immunosuppressive characteristics of CD101H neutrophils.