TY - JOUR
T1 - CD4+ 1 T cells alter the stromal microenvironment and repress medullary erythropoiesis in murine visceral leishmaniasis.
AU - Preham, Olivier Yvon Giuseppe
AU - Pinho, Flaviane Alves
AU - Pinto, Ana Isabel
AU - Rani, Gulab Fatima
AU - Brown, Najmeeyah
AU - Hitchcock, Ian Stuart
AU - Goto, Hiro
AU - Kaye, Paul
N1 - © 2018 Preham, Alves de Pinho, Pinto, Rani, Brown, Hitchcock, Goto and Kaye.
PY - 2018/12/18
Y1 - 2018/12/18
N2 - 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 IFNg-producing but not IFNg-deficient CD4+ T cells, mimicking the expansion of IFNg-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.
AB - 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 IFNg-producing but not IFNg-deficient CD4+ T cells, mimicking the expansion of IFNg-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.
KW - bone marrow
KW - erythropoiesis
KW - leishmaniasis
KW - macrophages
KW - stromal cells
UR - http://www.scopus.com/inward/record.url?scp=85059928178&partnerID=8YFLogxK
U2 - 10.3389/fimmu.2018.02958
DO - 10.3389/fimmu.2018.02958
M3 - Article
C2 - 30619317
SN - 1664-3224
VL - 9
JO - Frontiers in immunology
JF - Frontiers in immunology
M1 - 2958
ER -