Volume 43 Issue 3
May  2022
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Guang Wang, Yong-Feng Wang, Jiang-Lan Li, Ru-Ji Peng, Xin-Yin Liang, Xue-Dong Chen, Gui-Hua Jiang, Jin-Fang Shi, Yang-Hu Si-Ma, Shi-Qing Xu. Mechanism of hyperproteinemia-induced blood cell homeostasis imbalance in an animal model. Zoological Research, 2022, 43(3): 301-318. doi: 10.24272/j.issn.2095-8137.2021.397
Citation: Guang Wang, Yong-Feng Wang, Jiang-Lan Li, Ru-Ji Peng, Xin-Yin Liang, Xue-Dong Chen, Gui-Hua Jiang, Jin-Fang Shi, Yang-Hu Si-Ma, Shi-Qing Xu. Mechanism of hyperproteinemia-induced blood cell homeostasis imbalance in an animal model. Zoological Research, 2022, 43(3): 301-318. doi: 10.24272/j.issn.2095-8137.2021.397

Mechanism of hyperproteinemia-induced blood cell homeostasis imbalance in an animal model

doi: 10.24272/j.issn.2095-8137.2021.397
#Authors contributed equally to this work
Funds:  This study was supported by the National Natural Science Foundation of China (31972625), China Postdoctoral Science Foundation (2020M681718), Priority Academic Program Development (PAPD) of Jiangsu Higher Education Institutions, Postgraduate Research & Practice Innovation Program of Jiangsu Province (KYCX21_2963), and China Agriculture Research System (CARS) of Ministry of Finance and Ministry of Agriculture and Rural Areas
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  • Corresponding author: E-mail: szsqxu@suda.edu.cn
  • Received Date: 2022-01-07
  • Accepted Date: 2022-03-03
  • Published Online: 2022-03-08
  • Publish Date: 2022-05-18
  • Hyperproteinemia is a metabolic disorder associated with increased plasma protein concentration (PPC) and is often clinically complicated by malignant diseases or severe infections. At present, however, research on the molecular mechanism underlying high PPC (HPPC) is scant. Here, an animal model of primary hyperproteinemia was constructed in an invertebrate (Bombyx mori) to investigate the effects of HPPC on circulating blood cells. Results showed that HPPC affected blood cell homeostasis, leading to increased reactive oxygen species levels, and induced programmed cell death dependent on the endoplasmic reticulum-calcium ion signaling pathway. HPPC induced the proliferation of blood cells, mainly granulocytes, by activating the Janus kinase/signal transducer and activator of transcription (JAK/STAT) signaling pathway. Supplementation with the endocrine hormone active substance 20E significantly reduced the impact of HPPC on blood cell homeostasis. Thus, we identified a novel signaling pathway by which HPPC affects blood cell homeostasis, which differs from hyperglycemia, hyperlipidemia, and hypercholesterolemia. In addition, we showed that down-regulation of gene expression of the hematopoietic factor Gcm could be used as a potential early detection indicator for hyperproteinemia.
  • #Authors contributed equally to this work
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  • [1]
    Abbas MN, Kausar S, Sun YX, Tian JW, Zhu BJ, Liu CL. 2018. Suppressor of cytokine signaling 6 can enhance epidermal growth factor receptor signaling pathway in Bombyx mori (Dazao). Developmental & Comparative Immunology, 81: 187−192.
    Abuzaid AA, Aldahan MA, Helal MAA, Assiri AM, Alzahrani MH. 2020. Visceral leishmaniasis in Saudi Arabia: from hundreds of cases to zero. Acta Tropica, 212: 105707. doi: 10.1016/j.actatropica.2020.105707
    Adler BJ, Kaushansky K, Rubin CT. 2014. Obesity-driven disruption of haematopoiesis and the bone marrow niche. Nature Reviews Endocrinology, 10(12): 737−748. doi: 10.1038/nrendo.2014.169
    Aguilar-Ballester M, Herrero-Cervera A, Vinué Á, Martínez-Hervás S, González-Navarro H. 2020. Impact of cholesterol metabolism in immune cell function and atherosclerosis. Nutrients, 12(7): 2021. doi: 10.3390/nu12072021
    Bagchi S, He Y, Zhang H, Cao L, Van Rhijn I, Moody DB, et al. 2017. CD1b-autoreactive T cells contribute to hyperlipidemia-induced skin inflammation in mice. The Journal of Clinical Investigation, 127(6): 2339−2352. doi: 10.1172/JCI92217
    Barrett TJ, Distel E, Murphy AJ, Hu JY, Garshick MS, Ogando Y, et al. 2019. Apolipoprotein AI) promotes atherosclerosis regression in diabetic mice by suppressing myelopoiesis and plaque inflammation. Circulation, 140(14): 1170−1184. doi: 10.1161/CIRCULATIONAHA.119.039476
    Bataillé L, Augé B, Ferjoux G, Haenlin M, Waltzer L. 2005. Resolving embryonic blood cell fate choice in Drosophila: interplay of GCM and RUNX factors. Development, 132(20): 4635−4644. doi: 10.1242/dev.02034
    Bazzi W, Cattenoz PB, Delaporte C, Dasari V, Sakr R, Yuasa Y, et al. 2018. Embryonic hematopoiesis modulates the inflammatory response and larval hematopoiesis in Drosophila. Elife, 7: e34890.
    Bergstedt J, Lingen C. 1957. Cirrhosis of the liver in two children with hyperproteinaemia. Acta Paediatrica, 46(2): 185−190. doi: 10.1111/j.1651-2227.1957.tb08643.x
    Boyle TE, Holowaychuk MK, Adams AK, Marks SL. 2011. Treatment of three cats with hyperviscosity syndrome and congestive heart failure using plasmapheresis. Journal of the American Animal Hospital Association, 47(1): 50−55. doi: 10.5326/JAAHA-MS-5635
    Chang SH, Gumbel J, Luo SH, Thomas TS, Sanfilippo KM, Luo JQ, et al. 2019. Post-MGUS diagnosis serum monoclonal-protein velocity and the progression of monoclonal gammopathy of undetermined significance to multiple myeloma. Cancer Epidemiology, Biomarkers & Prevention, 28(12): 2055−2061.
    Chen XD, Wang YF, Wang YL, Li QY, Ma HY, Wang L, et al. 2018. Induced hyperproteinemia and its effects on the remodeling of fat bodies in silkworm. Bombyx mori. Frontiers in Physiology, 9: 302.
    Chistiakov DA, Grechko AV, Myasoedova VA, Melnichenko AA, Orekhov AN. 2018. The role of monocytosis and neutrophilia in atherosclerosis. Journal of Cellular and Molecular Medicine, 22(3): 1366−1382. doi: 10.1111/jcmm.13462
    Chong PSY, Chng WJ, De Mel S. 2019. STAT3: a promising therapeutic target in multiple myeloma. Cancers, 11(5): 731. doi: 10.3390/cancers11050731
    Cui SS, Lv X, Li W, Li ZS, Liu H, Gao YX, et al. 2018. Folic acid modulates VPO1 DNA methylation levels and alleviates oxidative stress-induced apoptosis in vivo and in vitro. Redox Biology, 19: 81–91.
    da Costa Oliveira V, Mendes Junior AAV, de Holanda Cavalcanti MC, de Fátima Madeira M, Ferreira LC, Figueiredo FB, et al. 2019. First description of parasite load and clinicopathological and anatomopathological changes in a dog naturally coinfected with Dioctophyme renale and Leishmania infantum in Brazil. Veterinary Parasitology:Regional Studies and Reports, 18: 100351. doi: 10.1016/j.vprsr.2019.100351
    Dodington DW, Desai HR, Woo M. 2018. JAK/STAT - emerging players in metabolism. Trends in Endocrinology & Metabolism, 29(1): 55−65.
    Flynn MC, Kraakman MJ, Tikellis C, Lee MKS, Hanssen NMJ, Kammoun HL, et al. 2020. Transient intermittent hyperglycemia accelerates atherosclerosis by promoting myelopoiesis. Circulation Research, 127(7): 877−892. doi: 10.1161/CIRCRESAHA.120.316653
    Fuchs Y, Steller H. 2015. Live to die another way: modes of programmed cell death and the signals emanating from dying cells. Nature Reviews Molecular Cell Biology, 16(6): 329−344. doi: 10.1038/nrm3999
    Fujii M, Sato Y, Ohara N, Hashimoto K, Kobashi H, Koyama Y, et al. 2014. Systemic IgG4-related disease with extensive peripheral nerve involvement that progressed from localized IgG4-related lymphadenopathy: an autopsy case. Diagnostic Pathology, 9: 41. doi: 10.1186/1746-1596-9-41
    Galluzzi L, Vitale I, Aaronson SA, Abrams JM, Adam D, Agostinis P, et al. 2018. Molecular mechanisms of cell death: recommendations of the Nomenclature Committee on Cell Death 2018. Cell Death & Differentiation, 25(3): 486−541.
    Gerin F, Ramazan DC, Baykan O, Sirikci O, Haklar G. 2014. Abnormal gel flotation in a patient with apperant pneumonia diagnosis: a case report. Biochemia Medica, 24(1): 180−182.
    Gu QL, Yang XJ, Lv J, Zhang JX, Xia B, Kim JD, et al. 2019. AIBP-mediated cholesterol efflux instructs hematopoietic stem and progenitor cell fate. Science, 363(6431): 1085−1088. doi: 10.1126/science.aav1749
    Hao YG, Jin LH. 2017. Dual role for Jumu in the control of hematopoietic progenitors in the Drosophila lymph gland. Elife, 6: e25094. doi: 10.7554/eLife.25094
    He Y, Xu X, Qiu JF, Yin WM, Sima YH, Xu SQ. 2020. Bombyx mori used as a fast detection model of liver melanization after a clinical drug – Acetaminophen exposure. Journal of Asia-Pacific Entomology, 23(1): 177−185. doi: 10.1016/j.aspen.2019.11.009
    Hu XL, Zhang X, Wang J, Huang ML, Xue RY, Cao GL, et al. 2015. Transcriptome analysis of BmN cells following over-expression of BmSTAT. Molecular Genetics and Genomics, 290(6): 2137–2146.
    Huang L, Liu D, Wang N, Ling SP, Tang YT, Wu J, et al. 2018. Integrated genomic analysis identifies deregulated JAK/STAT-MYC-biosynthesis axis in aggressive NK-cell leukemia. Cell Research, 28(2): 172−186. doi: 10.1038/cr.2017.146
    Hussain A, Almenfi HF, Almehdewi AM, Hamza MS, Bhat MS, Vijayashankar NP. 2019. Laboratory features of newly diagnosed multiple myeloma patients. Cureus, 11(5): e4716.
    Ishii K, Adachi T, Hamamoto H, Sekimizu K. 2014. Serratia marcescens suppresses host cellular immunity via the production of an adhesion-inhibitory factor against immunosurveillance cells. Journal of Biological Chemistry, 289(9): 5876−5888. doi: 10.1074/jbc.M113.544536
    Khan IM, Pokharel Y, Dadu RT, Lewis DE, Hoogeveen RC, Wu HZ, et al. 2016. Postprandial monocyte activation in individuals with metabolic syndrome. The Journal of Clinical Endocrinology and Metabolism, 101(11): 4195−4204. doi: 10.1210/jc.2016-2732
    Kitazawa A, Koda R, Yoshino A, Ueda Y, Takeda T. 2018. An IgA1-lambda-type monoclonal immunoglobulin deposition disease associated with membranous features in a patient with IgG4-related kidney disease: a case report. BMC Nephrology, 19(1): 330. doi: 10.1186/s12882-018-1133-9
    Kluck GEG, Wendt CHC, Imperio GED, Araujo MFC, Atella TC, Da Rocha I, et al. 2019. Plasmodium infection induces dyslipidemia and a hepatic lipogenic state in the host through the inhibition of the AMPK-ACC pathway. Scientific Reports, 9(1): 14695. doi: 10.1038/s41598-019-51193-x
    Koranteng F, Cha N, Shin M, Shim J. 2020. The role of lozenge in Drosophila hematopoiesis. Molecules and Cells, 43(2): 114−120.
    Kraakman MJ, Lee MKS, Al-Sharea A, Dragoljevic D, Barrett TJ, Montenont E, et al. 2017. Neutrophil-derived S100 calcium-binding proteins A8/A9 promote reticulated thrombocytosis and atherogenesis in diabetes. The Journal of Clinical Investigation, 127(6): 2133−2147. doi: 10.1172/JCI92450
    Laforge M, Elbim C, Frère C, Hémadi M, Massaad C, Nuss P, et al. 2020. Tissue damage from neutrophil-induced oxidative stress in COVID-19. Nature Reviews Immunology, 20(9): 515−516. doi: 10.1038/s41577-020-0407-1
    Lebestky T, Chang T, Hartenstein V, Banerjee U. 2000. Specification of Drosophila hematopoietic lineage by conserved transcription factors. Science, 288(5463): 146−149. doi: 10.1126/science.288.5463.146
    Li KL, Zhang YH, Xing R, Zhou YF, Chen XD, Wang H, et al. 2017. Different toxicity of cadmium telluride, silicon, and carbon nanomaterials against hemocytes in silkworm. Bombyx mori. RSC Advances, 7(79): 50317−50327.
    Ling E, Shirai K, Kanekatsu R, Kiguchi K. 2005. Hemocyte differentiation in the hematopoietic organs of the silkworm, Bombyx mori: prohemocytes have the function of phagocytosis. Cell and Tissue Research, 320(3): 535−543. doi: 10.1007/s00441-004-1038-8
    Ling EJ, Shirai K, Kanekatsu R, Kiguchi K. 2003. Classification of larval circulating hemocytes of the silkworm, Bombyx mori, by acridine orange and propidium iodide staining. Histochemistry and Cell Biology, 120(6): 505−511. doi: 10.1007/s00418-003-0592-6
    Liu T, Xing R, Zhou YF, Zhang J, Su YY, Zhang KQ, et al. 2014. Hematopoiesis toxicity induced by CdTe quantum dots determined in an invertebrate model organism. Biomaterials, 35(9): 2942−2951. doi: 10.1016/j.biomaterials.2013.12.007
    Manning RD Jr. 1987. Renal hemodynamic, fluid volume, and arterial pressure changes during hyperproteinemia. The American Journal of Physiology, 252(3 Pt 2): F403–F411.
    Manning RD Jr. 1992. Chronic effects of hyperproteinemia on blood volume and lymph protein concentration. The American Journal of Physiology, 262(4 Pt 2): H937–H941.
    Manning RD Jr. 1998a. Chronic lymph flow responses to hyperproteinemia. The American Journal of Physiology, 275(1): R135−R140.
    Manning RD Jr. 1998b. Dynamics of extracellular fluid volume changes during hyperproteinemia. The American Journal of Physiology, 275(6): R1878−R1884.
    Mattisson IY, Björkbacka H, Wigren M, Edsfeldt A, Melander O, Fredrikson GN, et al. 2017. Elevated markers of death receptor-activated apoptosis are associated with increased risk for development of diabetes and cardiovascular disease. eBioMedicine, 26: 187−197. doi: 10.1016/j.ebiom.2017.11.023
    Nagareddy PR, Murphy AJ, Stirzaker RA, Hu YY, Yu S, Miller RG, et al. 2013. Hyperglycemia promotes myelopoiesis and impairs the resolution of atherosclerosis. Cell Metabolism, 17(5): 695−708. doi: 10.1016/j.cmet.2013.04.001
    Nakahara Y, Kanamori Y, Kiuchi M, Kamimura M. 2010. Two hemocyte lineages exist in silkworm larval hematopoietic organ. PLoS One, 5(7): e11816. doi: 10.1371/journal.pone.0011816
    Qiu JF, Li X, Cui WZ, Liu XF, Tao H, Yang K, et al. 2019. Inhibition of period gene expression causes repression of cell cycle progression and cell growth in the Bombyx mori cells. Frontiers in Physiology, 10: 537. doi: 10.3389/fphys.2019.00537
    Peng JK, Cao GL, Qian Y, Zhang XL, Ma HY, He L, et al. 2012. Cloning and Sequence Analysis of JAK/STAT Pathway Related Major Genes of Silkworm (Bombyx mori). Scientia Agricultura Sinica, 45(17): 3592−3601.
    Raivola J, Haikarainen T, Silvennoinen O. 2020. Characterization of JAK1 pseudokinase domain in cytokine signaling. Cancers, 12(1): 78.
    Ren ZH, Ahn JH, Liu HQ, Tsai YH, Bhanu NV, Koss B, et al. 2019. PHF19 promotes multiple myeloma tumorigenicity through PRC2 activation and broad H3K27me3 domain formation. Blood, 134(14): 1176−1189. doi: 10.1182/blood.2019000578
    Rendra E, Riabov V, Mossel DM, Sevastyanova T, Harmsen MC, Kzhyshkowska J. 2019. Reactive oxygen species (ROS) in macrophage activation and function in diabetes. Immunobiology, 224(2): 242−253. doi: 10.1016/j.imbio.2018.11.010
    Riemer F, Kuehner KA, Ritz S, Sauter-Louis C, Hartmann K. 2016. Clinical and laboratory features of cats with feline infectious peritonitis-a retrospective study of 231 confirmed cases (2000–2010). Journal of Feline Medicine and Surgery, 18(4): 348−356. doi: 10.1177/1098612X15586209
    Sant C, Thomas S, Wint C, Maharaj V, Kalloo N, Hosein A. 2020. A case of Pearsonema eggs in the urine sediment of a cat in Trinidad. Veterinary Parasitology:Regional Studies and Reports, 22: 100491. doi: 10.1016/j.vprsr.2020.100491
    Sarrazy V, Viaud M, Westerterp M, Ivanov S, Giorgetti-Peraldi S, Guinamard R, et al. 2016. Disruption of glut1 in hematopoietic stem cells prevents myelopoiesis and enhanced glucose flux in atheromatous plaques of ApoE-/- Mice. Circulation Research, 118(7): 1062−1077. doi: 10.1161/CIRCRESAHA.115.307599
    Silwal P, Kim JK, Kim YJ, Jo EK. 2020. Mitochondrial reactive oxygen species: double-edged weapon in host defense and pathological inflammation during infection. Frontiers in Immunology, 11: 1649. doi: 10.3389/fimmu.2020.01649
    Simion V, Zhou HY, Haemmig S, Pierce JB, Mendes S, Tesmenitsky Y, et al. 2020. A macrophage-specific lncRNA regulates apoptosis and atherosclerosis by tethering HuR in the nucleus. Nature Communications, 11(1): 6135. doi: 10.1038/s41467-020-19664-2
    Steinberger BA, Ford SM, Coleman TA. 2003. Intravenous immunoglobulin therapy results in post-infusional hyperproteinemia, increased serum viscosity, and pseudohyponatremia. American Journal of Hematology, 73(2): 97−100. doi: 10.1002/ajh.10325
    Tabunoki H, Bono H, Ito K, Yokoyama T. 2016. Can the silkworm (Bombyx mori) be used as a human disease model?. Drug Discoveries & Therapeutics, 10(1): 3−8.
    Trébuchet G, Cattenoz PB, Zsámboki J, Mazaud D, Siekhaus DE, Fanto M, et al. 2019. The repo homeodomain transcription factor suppresses hematopoiesis in Drosophila and preserves the glial fate. Journal of Neuroscience, 39(2): 238−255. doi: 10.1523/JNEUROSCI.1059-18.2018
    Vion AC, Kheloufi M, Hammoutene A, Poisson J, Lasselin J, Devue C, et al. 2017. Autophagy is required for endothelial cell alignment and atheroprotection under physiological blood flow. Proceedings of the National Academy of Sciences of the United States of America, 114(41): E8675−E8684.
    Wagner R, Heni M, Tabák AG, Machann J, Schick F, Randrianarisoa E, et al. 2021. Pathophysiology-based subphenotyping of individuals at elevated risk for type 2 diabetes. Nature Medicine, 27(1): 49−57. doi: 10.1038/s41591-020-1116-9
    Wang YF, Chen XD, Wang G, Li QY, Liang XY, Sima YH, et al. 2019. Influence of hyperproteinemia on reproductive development in an invertebrate model. International Journal of Biological Sciences, 15(10): 2170−2181. doi: 10.7150/ijbs.33310
    Wang YF, Wang G, Li JL, Qu YX, Liang XY, Chen XD, et al. 2021. Influence of hyperproteinemia on insect innate immune function of the circulatory system in Bombyx mori. Biology, 10(2): 112.
    West AP, Brodsky IE, Rahner C, Woo DK, Erdjument-Bromage H, Tempst P, et al. 2011. TLR signalling augments macrophage bactericidal activity through mitochondrial ROS. Nature, 472(7344): 476−480. doi: 10.1038/nature09973
    Xi H, Zhang YL, Xu YJ, Yang WY, Jiang XH, Sha XJ, et al. 2016. Caspase-1 inflammasome activation mediates homocysteine-induced pyrop-apoptosis in endothelial cells. Circulation Research, 118(10): 1525−1539. doi: 10.1161/CIRCRESAHA.116.308501
    Xie K, Tian L, Guo XY, Li K, Li JP, Deng XJ, et al. 2016. BmATG5 and BmATG6 mediate apoptosis following autophagy induced by 20-hydroxyecdysone or starvation. Autophagy, 12(2): 381−396. doi: 10.1080/15548627.2015.1134079
    Xu M, Wang X, Tan J, Zhang K, Guan X, Patterson LH, et al. 2015. A novel Lozenge gene in silkworm, Bombyx mori regulates the melanization response of hemolymph. Developmental & Comparative Immunology, 53(1): 191−198.
    Zhang K, Tan J, Hao XW, Tang HY, Abbas MN, Su JJ, et al. 2021. Bombyx mori U-shaped regulates the melanization cascade and immune response via binding with the Lozenge protein. Insect Science,doi: 10.1111/1744-7917.12959.
    Zhang M, Zhu HP, Ding Y, Liu ZY, Cai ZJ, Zou MH. 2017. AMP-activated protein kinase α1 promotes atherogenesis by increasing monocyte-to-macrophage differentiation. Journal of Biological Chemistry, 292(19): 7888−7903. doi: 10.1074/jbc.M117.779447
    Zhao H, Li Y, He LJ, Pu WJ, Yu W, Li Y, et al. 2020. In vivo AAV-CRISPR/Cas9-mediated gene editing ameliorates atherosclerosis in familial hypercholesterolemia. Circulation, 141(1): 67−79. doi: 10.1161/CIRCULATIONAHA.119.042476
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