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

Abstract

PLOS Neglected Tropical Diseases | https://doi.funders had no role in study design, data collection and leishmaniasis caused by Leishmania major and visceral leishmaniasis caused by L. donovani, the molecule showed distinct roles in protection/pathology; although the molecule was protective against L. major infection, depletion of the molecule resulted in easing the pathology during L. donovani infection. These may prove the complexity of MRP14, but at the same time support understanding of the mechanisms behind the complexity.Myeloid-related protein (MRP) 14, also known as S100A9, belongs to the S100 calcium-binding protein family and can form the heterodimer with MRP8, which is known as S100A8 [1,2]. S100 protein family proteins contain two Ca 2+ -binding regions known as EF-hands and play a role in cell differentiation, cell cycle progression, regulation of kinase activity, and cytoskeletalmembrane interactions when Ca2 + bind [3]. The expression of MRP14 and MRP8 is specific for myeloid cells such as granulocytes, monocytes and macrophages in inflamed tissue [4]. They are abundant cytoplasmic proteins of neutrophils and monocytes [1,5], and also known as markers of inflammatory macrophages. MRP14 expression is abundant in immature monocytes and is lost as the cells terminally differentiate into tissue macrophages, so MRP14 can be associated with monocytic differentiation [6].MRP14 has been characterized as an inflammation-related protein [7][8][9]. Extracellular MRP14 and MRP8 are known to function as damage-associated molecular patterns (DAMP), which are endogenous molecules or alarmins released after cell activation or necrotic cells and are secreted by the inflammatory cells when activated [10]. Neither MRP14 nor MRP8 has a signal sequence for secretion via classical ER/Golgi route, but it is demonstrated that these proteins are secreted after activation of protein kinase C via tubulin-dependent pathway [10]. Extracellular MRP14 and MRP8 bind Toll-like receptor (TLR) 2, TLR4 and receptor for advanced glycation endproducts (RAGE) and induce cell recruitment and cell activation [11][12][13][14]. It is also reported that MRP14 promotes inflammatory process in infection and autoimmunity via TLR4 [9,12,15], and cell growth in cancer and cell migration via RAGE [16,17]. Actually, MRP8 and MRP14 in serum are elevated in various diseases [18][19][20]. In inflammatory diseases such as rheumatoid arthritis, psoriatic arthritis, and coronary syndromes, the accumulation of cells expressing MRP14 or MRP8 is observed at inflammatory sites [18,[21][22][23]. Therefore, it is considered that MRP14 plays a critical role in the pathogenesis in these diseases. In malaria, we reported that macrophages expressing MRP14 accumulated in the spleen and liver of BALB/c mice and MRP14 level in the plasma was also elevated during Plasmodium berghei ANKA infection [24]. In addition, the administration of recombinant MRP14 exacerbated hepatic injury and promoted the up-regulation of pro-inflammatory molecules in the liver [11]. These re...

Hepatomegaly Associated with Non-Obstructive Sinusoidal Dilation in Experimental Visceral Leishmaniasis

“…Firstly, splenomegaly during experimental VL is accompanied by an increase in cell numbers [30], whilst hepatomegaly is not -as demonstrated in the present study. Secondly, our previous studies using genetically modified mice demonstrated that deficiency in host molecules BAFF and MRP14 leads to attenuation of splenomegaly, but not hepatomegaly, in L. donovani infection [30,31]. Although it is known that dysfunction or damage in the liver or the spleen often affects the other, the influence of L. donovani infection on these organs does not appear very closely connected.…”

Inflammatory CD11b+ Macrophages Produce BAFF in Spleen of Mice Infected with Leishmania donovani

“…In a previous study, we have reported that inflammatory macrophages expressing MRP8 and MRP14 accumulate in the spleen during L . donovani infection [ 28 ]. To reveal the relationship between the MRP8/14-expressing macrophages and the BAFF-producing CD11b + MN cells, the CD11b-positive or -negative fraction of the splenocytes from L .…”

“…Later, we also found an accumulation of MRP8 + mononuclear cells in the spleen of L . donovani -infected mice [ 28 ]. Because of the shared expression of MRP8/MRP14 and shared morphological characteristics in the accumulated mononuclear cells between L .…”

“…On the other hand, we found that macrophages expressing MRP8 and MRP14 are less infected compared with MRP8/MRP14-negative cells in the spleen chronically infected with L . donovani [ 28 ]. We also found that heavily infected macrophages have low expression levels of CD11b in the spleen of mice chronically infected with L .…”

“…The CD11b + MN cells in the red pulp had relatively wide cytoplasm, sharing morphological characteristics with macrophages and distinct from lymphocytes. In a previous study, we have reported that inflammatory macrophages expressing MRP8 and MRP14 accumulate in the spleen during L. donovani infection [28]. To reveal the relationship between the MRP8/14-expressing macrophages and the BAFFproducing CD11b + MN cells, the CD11b-positive or -negative fraction of the splenocytes from L. donovani-infected mice was analyzed for expression of MRP14 by Western blotting.…”