Pathological roles of MRP14 in anemia and splenomegaly during experimental visceral leishmaniasis.

Myeloid-related protein 14 (MRP14) belongs to the S100 calcium-binding protein family and is expressed in neutrophils and inflammatory macrophages. Increase in the number of MRP14+ cells or serum level of MRP14 is associated with various diseases such as autoimmune diseases and infectious diseases, suggesting the involvement of the molecule in pathogenesis of those diseases. In this study, to examine the pathological involvement of MRP14 during cutaneous and visceral leishmaniasis, wild-type (WT) and MRP14 knockout (MRP14KO) mice were infected with Leishmania major and L. donovani. Increase in the number of MRP14+ cells at the infection sites in wild-type mice was commonly found in the skin during L. major infection as well as the spleen and liver during L. donovani infection. In contrast, the influence of MRP14 to the pathology seemed different between the two infections. MRP14 depletion exacerbated the lesion development and ulcer formation in L. major infection. On the other hand, the depletion improved anemia and splenomegaly but not hepatomegaly at 24 weeks of L. donovani infection. These results suggest that, distinct from its protective role in CL, MRP14 is involved in exacerbation of some symptoms during VL.

Exacerbation of hepatic injury during rodent malaria by myeloid-related protein 14.

Hepatic dysfunction is one of the clinical features in severe malaria. However, the mechanism of hepatic injury during malaria is still unknown. Myeloid-related protein (MRP) 14 is abundantly expressed by myeloid cells and involved in various inflammatory diseases. We previously reported that serum MRP14 is elevated in mice infected with Plasmodium berghei ANKA. In order to verify whether extracellular MRP14 is involved in the pathology of hepatic injury during rodent malaria, we intravenously administrated recombinant MRP14 (rMRP14) to mice infected with P. berghei ANKA. The administration of rMRP14 did not affect parasite number or hematocrit. On the other hand, the hepatic injury was exacerbated in rMRP14-treated mice, and their serum concentration of hepatic enzymes increased significantly more than PBS-treated controls. Immunohistochemical analysis of the liver showed that more MRP14+ macrophages accumulated in rMRP14-treated mice than PBS-treated controls after infection. The administration of rMRP14 also promotes the up-regulation of pro-inflammatory molecules in the liver, such as iNOS, IL-1ß, IL-12, and TNF-α. Even in the absence of Plasmodium infection, administration of rMRP14 could induce the accumulation of MRP14+ macrophages and up-regulation of the pro-inflammatory molecules in the liver of naïve mice. The results indicate that MRP14 promotes the accumulation of MRP14+ cells and the up-regulation of pro-inflammatory molecules and NO, which amplify inflammatory cascade leading to hepatic injury. In conclusion, MRP14 is a one of key molecules for liver inflammation during rodent malaria.

MRP14 is dispensable for LPS-induced shock in BALB/c mice.

Myeloid-related protein (MRP) 14 and MRP8 are abundantly expressed by myeloid cells and are involved in various inflammatory disorders. Although accumulating evidence revealed the roles of MRP14 and MRP8 in inflammatory responses by using MRP14-knockout (KO) mice, the KO mice were only available in the C57BL/6 background. We established BALB/c-background MRP14-KO mice to examine if its biological functions are conserved in mice with a different genetic background. MRP14-KO BALB/c mice showed different phenotypes from the reported MRP14-KO C57BL/6 mice in terms of bone marrow cell response to LPS and peripheral leukocyte population. When an acute lethal dose of LPS was injected, the survival rate was not different between MRP14-KO and WT mice, which was also different from results previously reported on C57BL/6 mice. These results suggest that immunological functions of MRP14, and possibly also the associated molecule MRP8, are different between BALB/c and C57BL/6 mice, at least in the response to LPS.