Hemophagocytosis in Experimental Visceral Leishmaniasis by Leishmania donovani

Morimoto, Ayako; Omachi, Satoko; Osada, Yuko; Chambers, James K.; Uchida, Katsuhisa; Sanjoba, Chizu; Matsumoto, Yoshitsugu; Goto, Yasuyuki

doi:10.1371/journal.pntd.0004505

Cited by 25 publications

(47 citation statements)

References 41 publications

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“…A similar result has been reported in L. amazonensis infection; CD11b + cells but not F4/80 + cells are dominant infected cells in the infected footpad [42]. In contrast, infected macrophages in the spleen are F4/80 + [43], but not MRP14 + or MRP8 + during L. donovani infection (Fig 1).…”

Section: Discussionsupporting

confidence: 87%

“…It is well known that these two molecules contribute to control of CL [45,46], whereas they may promote anemia during VL. We previously reported that infected macrophages in the spleen engulf erythrocytes during VL and proposed that the phenomenon, called hemophagocytosis, is one of the possible causes of anemia during VL [43]. Hemophagocytosis results from hyper-activation of macrophages by The role of MRP14 in experimental visceral leishmaniasis many reasons.…”

Section: Discussionmentioning

confidence: 99%

“…Hemophagocytosis results from hyper-activation of macrophages by The role of MRP14 in experimental visceral leishmaniasis many reasons. In the case of VL, most of the hemophagocytes in the spleen were multinucleated giant cells (MGC) heavily infected with L. donovani [43]. IFN-γ has a crucial role in MGC formation [47].…”

Section: Discussionmentioning

confidence: 99%

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

et al. 2020

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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...

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Section: Discussionsupporting

confidence: 87%

Section: Discussionmentioning

confidence: 99%

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

et al. 2020

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“…Various mechanisms have been proposed to underpin the development of VL-associated pancytopenia, including auto-immune destruction of erythrocytes, platelets and leukocytes, or BM failure (18). Anemia has been attributed to aberrant sialoglycosylation of red blood cells (19), altered recognition of band 3 subsequent to oxidative stress (20) or enhanced macrophage-mediated erythrophagocytosis (21).…”

Section: Introductionmentioning

confidence: 99%

CD4+ T Cells Alter the Stromal Microenvironment and Repress Medullary Erythropoiesis in Murine Visceral Leishmaniasis

Preham¹,

Pinho²,

Pinto³

et al. 2018

Front. Immunol.

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Human visceral leishmaniasis, a parasitic disease of major public health importance in developing countries, is characterized by variable degrees of severity of anemia, but the mechanisms underlying this change in peripheral blood have not been thoroughly explored. Here, we used an experimental model of visceral leishmaniasis in C57BL/6 mice to explore the basis of anemia following infection with Leishmania donovani. 28 days post-infection, mice showed bone marrow dyserythropoiesis by myelogram, with a reduction of TER119+ CD71−/+ erythroblasts. Reduction of medullary erythropoiesis coincided with loss of CD169high bone marrow stromal macrophages and a reduction of CXCL12-expressing stromal cells. Although the spleen is a site of extramedullary erythropoiesis and erythrophagocytosis, splenectomy did not impact the extent of anemia or affect the repression of medullary hematopoiesis that was observed in infected mice. In contrast, these changes in bone marrow erythropoiesis were not evident in B6.Rag2−/− mice, but could be fully reconstituted by adoptive transfer of IFNγ-producing but not IFNγ-deficient CD4+ T cells, mimicking the expansion of IFNγ-producing CD4+ T cells that occurs during infection in wild type mice. Collectively, these data indicate that anemia during experimental murine visceral leishmaniasis can be driven by defects associated with the bone marrow erythropoietic niche, and that this represents a further example of CD4+ T cell-mediated immunopathology affecting hematopoietic competence.

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“…Typhimurium infections were shown to result in anemia and lead to the development of hemophagocytic macrophages, related to IFNG and IL-12-induced iron efflux from tissues [ 58 ]. The mechanisms activating the macrophage to engulf erythrocytes are not fully described, but there is some evidence suggesting that pro-inflammatory cytokines produced by the immune response to the ongoing infections, such as IFNG and TNF, stimulate macrophages to phagocytize erythrocytes, which in turn causes the development of anemia and other hematologic disorders [ 110 , 111 ]. In the absence of infections, the prolonged infusion of IFNG led to the appearance of hemophagocytic macrophages and the subsequent development of anemia [ 112 , 113 ].…”

Section: Nutritional Immunity and Infection-induced Anemiamentioning

confidence: 99%

Modulation of Iron Metabolism in Response to Infection: Twists for All Tastes

et al. 2018

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Iron is an essential nutrient for almost all living organisms, but is not easily made available. Hosts and pathogens engage in a fight for the metal during an infection, leading to major alterations in the host’s iron metabolism. Important pathological consequences can emerge from the mentioned interaction, including anemia. Several recent reports have highlighted the alterations in iron metabolism caused by different types of infection, and several possible therapeutic strategies emerge, based on the targeting of the host’s iron metabolism. Here, we review the most recent literature on iron metabolism alterations that are induced by infection, the consequent development of anemia, and the potential therapeutic approaches to modulate iron metabolism in order to correct iron-related pathologies and control the ongoing infection.

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Hemophagocytosis in Experimental Visceral Leishmaniasis by Leishmania donovani

Cited by 25 publications

References 41 publications

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

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

CD4+ T Cells Alter the Stromal Microenvironment and Repress Medullary Erythropoiesis in Murine Visceral Leishmaniasis

Modulation of Iron Metabolism in Response to Infection: Twists for All Tastes

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