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Phagocyte Biology and its Disorders
Senescence-accelerated mice (SAMP1/TA-1) treated repeatedly with lipopolysaccharide develop a condition that resembles hemophagocytic lymphohistiocytosis
Ferrata Storti Foundation
Haematologica 2019 Volume 10410):1995-2005
Isao Tsuboi,1,3 Tomonori Harada,1 Yoko Hirabayashi2 and Shin Aizawa1
1Division of Anatomical Science, Department of Functional Morphology, Nihon University School of Medicine, Tokyo and 2Cellular and Molecular Toxicology Division, National Center for Biological Safety and Research, National Institute of Health Science, Kawasaki, Japan
ABSTRACT
Hemophagocytic lymphohistiocytosis is a life-threatening systemic hyperinflammatory disorder with primary and secondary forms. Primary hemophagocytic lymphohistiocytosis is associated with inherited defects in various genes that affect the immunological cytolytic pathway. Secondary hemophagocytic lymphohistiocytosis is not inherited, but complicates various medical conditions including infections, autoin- flammatory/autoimmune diseases, and malignancies. When senescence- accelerated mice (SAMP1/TA-1) with latent deterioration of immunological function and senescence-resistant control mice (SAMR1) were treated repeatedly with lipopolysaccharide, SAMP1/TA-1 mice displayed the clini- copathological features of hemophagocytic lymphohistiocytosis such as hepatosplenomegaly, pancytopenia, hypofibrinogenemia, hyperferritine- mia, and hemophagocytosis. SAMR1 mice showed no features of hemo- phagocytic lymphohistiocytosis. Lipopolysaccharide induced upregulation of proinflammatory cytokines such as interleukin-1β, interleukin-6, tumor necrosis factor-α, and interferon-g, and interferon-g-inducible chemokines such as c-x-c motif chemokine ligands 9 and 10 in the liver and spleen in both SAMP1/TA-1 and SAMR1 mice. However, upregulation of proinflam- matory cytokines and interferon-g-inducible chemokines in the liver persist- ed for longer in SAMP1/TA-1 mice than in SAMR1 mice. In addition, the magnitude of upregulation of interferon-g in the liver and spleen after lipopolysaccharide treatment was greater in SAMP1/TA-1 mice than in SAMR1 mice. Furthermore, lipopolysaccharide treatment led to a pro- longed increase in the proportion of peritoneal M1 macrophages and simul- taneously to a decrease in the proportion of M2 macrophages in SAMP1/TA-1 mice compared with SAMR1 mice. Lipopolysaccharide appeared to induce a hyperinflammatory reaction and prolonged inflamma- tion in SAMP1/TA-1 mice, resulting in features of secondary hemophago- cytic lymphohistiocytosis. Thus, SAMP1/TA-1 mice represent a useful mouse model to investigate the pathogenesis of bacterial infection-associ- ated secondary hemophagocytic lymphohistiocytosis.
Introduction
Hemophagocytic lymphohistiocytosis (HLH) is characterized by an unremitting activation of lymphocytes and macrophages that leads to an overwhelming inflam- matory reaction resulting in organ damage.1-3 HLH is broadly divided into primary HLH and secondary HLH (sHLH). Primary HLH is caused by mutations in genes such as PFR1, UNC13D, STX11, and STXBP2, which encode proteins involved in granule exocytosis.4-8 sHLH is associated with viral, bacterial, parasitic, or fungal infections, which cause strong activation of the immune system.1,2,9 sHLH also occurs in the context of autoimmune diseases such as systemic juvenile idiopathic arthritis, systemic lupus erythematosus, and Kawasaki disease and malignancies such as lymphoma.10-14 HLH is characterized by high fever, lymphoadenopathy,
Correspondence:
ISAO TSUBOI
tsuboi.isao@nihon-u.ac.jp
Received: October 17, 2018. Accepted: February 25, 2019. Pre-published: February 28, 2019.
doi:10.3324/haematol.2018.209551
Check the online version for the most updated information on this article, online supplements, and information on authorship & disclosures: www.haematologica.org/content/104/10/1995
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