Mast cells: Involvement in polycythemia vera-associated pruritus and strain-dependent expression of chymase

Mast cells are innate immune cells best known for their roles in allergic disorders as well as their protective functions in host defense against pathogens. Polycythemia vera (PV) is a clonal blood disorder characterized by excessive production of red blood cells, white blood cells, and platelets. Pruritus is a common symptom in PV, but the pathophysiology is unclear, and there is no effective treatment. By studying JAK2V617F transgenic mice that display PV-like phenotypes, we found that pruritus occurred in these animals as they aged. Pruritus was accompanied by massive accumulations of mast cells in the skin, which is consistent with the presence of significantly higher numbers of mast cell progenitors in the bone marrow, spleen, peripheral blood, and peritoneal cavity of JAK2V617F transgenic mice. Cultured mast cells from JAK2V617F transgenic mice displayed enhanced growth factor signaling. They were relatively resistant to cell death upon deprivation of growth factors and displayed a growth advantage over control cells under suboptimal growth conditions. We further identified a JAK2 inhibitor that inhibits mast cells and provides therapeutic benefits to pruritic JAK2V617F transgenic mice. Our study suggests that elevated levels of mast cells are involved in pruritus associated with PV and that JAK2 inhibitors are potential anti-pruritus drugs.;We also identified a congenic line of C57BL/6 mice that expressed an extraordinarily high level of mast cell chymases Mcp-2 and Mcp-4.This overexpression is associated with variant Mcp-2 and Mcp-4 genes originated from DBA/2 mice which we found also expressed a high level of Mcp-2 and Mcp-4.Further study revealed that Mcp-2 and Mcp-4 are selectively overexpressed as many other mast cell proteases are not affected. Chymases are involved in many pathological events including cardiovascular disorders and inflammation. We believe that the increased chymase activity may be responsible for the susceptibility of DBA/2 mice to development of atherosclerosis and autoimmune myocarditis. We thus generated a unique mouse model to study the function of chymases and their pathological implications.