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Horm Metab Res 2021; 53(01): 56-62
DOI: 10.1055/a-1250-8221
Endocrine Research

Blockade of CCL2/CCR2 Signaling Pathway Exerts Anti-Inflammatory Effects and Attenuates Gestational Diabetes Mellitus in a Genetic Mice Model

Xinying Qi
1   The Second Department of Obstetrics, Cangzhou Central Hospital, Cangzhou, Hebei, China
,
Yanping Xing
1   The Second Department of Obstetrics, Cangzhou Central Hospital, Cangzhou, Hebei, China
,
Xuezhen Wang
1   The Second Department of Obstetrics, Cangzhou Central Hospital, Cangzhou, Hebei, China
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Abstract

The chemokine (C-C motif) ligand 2 (CCL2) and its receptor CCR2 are involved in gestational diabetes mellitus (GDM). The present study aims to explore the effects of CCL2 blocking on GDM. Serum CCL2, interleukin (IL)-6, and tumor necrosis factor (TNF)-α were determined in GDM patients and healthy volunteers. C57BL/KsJdb/+mouse was used as the GDM model and CCL2 antibody (αCCL2) was applied. Flow cytometry was applied to determine the frequency of macrophages. Quantitative reverse transcription PCR (RT-qPCR) and western blot were determined to detect the mRNA and protein expressions, respectively. Enzyme-linked immunosorbent assay (ELISA) was applied to determine the levels of inflammatory cytokines and serum insulin. Serum CCL2 was correlated with inflammatory cytokines (IL-6 and TNF-α) in the GDM patients. Besides, the results showed high expressions of CCL2 in the visceral adipose tissue (VAT) and placenta tissue in the GDM mice. Flow cytometry and immunohistochemistry (IHC) staining showed the accumulations of macrophages in these tissues. Treatment of αCCL2 attenuated the GDM symptoms and ameliorated the inflammation. Furthermore, the treatment of αCCL2 improved reproductive outcomes in the GDM mice. Blockade of CCL2 attenuated GDM symptoms and reduced inflammatory cytokines in a genetic mice model.

Key words

gestational diabetes mellitus, diabetes - inflammation - inflammatory cytokines - CCL2 - CCR2

Supplementary Material



Publication History

Received: 27 May 2020

Accepted after revision: 25 August 2020

Article published online:
06 October 2020

© 2020. Thieme. All rights reserved.

Georg Thieme Verlag KG
Rüdigerstraße 14, 70469 Stuttgart, Germany

 

  • References

  • 1 Buchanan TA, Xiang AH. Gestational diabetes mellitus. J Clin Invest 2005; 115: 485-491
    CrossrefPubMedSearch in Google Scholar
  • 2 Yao D, Chang Q, Wu QJ. et al. Relationship between maternal central obesity and the risk of gestational diabetes mellitus: A systematic review and meta-analysis of cohort studies. J Diabetes Res 2020; 6303820
    PubMedSearch in Google Scholar
  • 3 Wang WJ, Zhang L, Zheng T. et al. Fetuin-A and fetal growth in gestational diabetes mellitus. BMJ Open Diabetes Res Care 2020; 8: e000864
    CrossrefPubMedSearch in Google Scholar
  • 4 Beucher G, Viaris de Lesegno B, Dreyfus M. Maternal outcome of gestational diabetes mellitus. J Gynecol Obstet Biol Reprod (Paris) 2010; 39: S171-S188
    CrossrefPubMedSearch in Google Scholar
  • 5 Williams VF, Oh GT, Stahlman S. et al. Diabetes mellitus and gestational diabetes, active and reserve component service members and dependents, 2008-2018. MSMR 2020; 27: 8-17
    PubMedSearch in Google Scholar
  • 6 Sert UY, Ozgu-Erdinc AS. Gestational diabetes mellitus screening and diagnosis. Adv Exp Med Biol 2020;
    CrossrefPubMedSearch in Google Scholar
  • 7 Pantham P, Aye IL, Powell TL. Inflammation in maternal obesity and gestational diabetes mellitus. Placenta 2015; 36: 709-715
    CrossrefPubMedSearch in Google Scholar
  • 8 Heitritter SM, Solomon CG, Mitchell GF. et al. Subclinical inflammation and vascular dysfunction in women with previous gestational diabetes mellitus. J Clin Endocrinol Metab 2005; 90: 3983-3988
    CrossrefPubMedSearch in Google Scholar
  • 9 Fujiwara N, Kobayashi K. Macrophages in inflammation. Curr Drug Targets Inflamm Allergy 2005; 4: 281-286
    CrossrefPubMedSearch in Google Scholar
  • 10 Aktulay A, Engin-Ustun Y, Ozkan MS. et al. Gestational diabetes mellitus seems to be associated with inflammation. Acta Clin Croat 2015; 54: 475-478
    PubMedSearch in Google Scholar
  • 11 Lekva T, Norwitz ER, Aukrust P. et al. Impact of systemic inflammation on the progression of gestational diabetes mellitus. Curr Diab Rep 2016; 16: 26
    CrossrefPubMedSearch in Google Scholar
  • 12 Skorzynska-Dziduszko KE, Kimber-Trojnar Z, Patro-Malysza J. et al. An interplay between obesity and inflammation in gestational diabetes mellitus. Curr Pharm Biotechnol 2016; 17: 603-613
    CrossrefPubMedSearch in Google Scholar
  • 13 Li C, Qiao B, Qi W. et al. Association of macrophage migration inhibitory factor polymorphisms with gestational diabetes mellitus in Han Chinese Women. Gynecol Obstet Invest 2016; 81: 84-89
    CrossrefPubMedSearch in Google Scholar
  • 14 Zheng L, Li C, Qi WH. et al. Expression of macrophage migration inhibitory factor gene in placenta tissue and its correlation with gestational diabetes mellitus. Zhonghua Yi Xue Za Zhi 2017; 97: 3388-3391
    PubMedSearch in Google Scholar
  • 15 Teler J, Tarnowski M, Safranow K. et al. CCL2, CCL5, IL4 and IL15 Gene polymorphisms in women with gestational diabetes mellitus. Horm Metab Res 2017; 49: 10-15
    Thieme ConnectPubMedSearch in Google Scholar
  • 16 Di Benedetto A, Russo GT, Corrado F. et al. Inflammatory markers in women with a recent history of gestational diabetes mellitus. J Endocrinol Invest 2005; 28: 34-38
    CrossrefPubMedSearch in Google Scholar
  • 17 Yang H, Wang J, Fan JH. et al. Ilexgenin A exerts anti-inflammation and anti-angiogenesis effects through inhibition of STAT3 and PI3K pathways and exhibits synergistic effects with Sorafenib on hepatoma growth. Toxicol Appl Pharmacol 2017; 315: 90-101
    CrossrefPubMedSearch in Google Scholar
  • 18 Daly C, Rollins BJ. Monocyte chemoattractant protein-1 (CCL2) in inflammatory disease and adaptive immunity: therapeutic opportunities and controversies. Microcirculation 2003; 10: 247-257
    CrossrefPubMedSearch in Google Scholar
  • 19 Ziraldo C, Vodovotz Y, Namas RA. et al. Central role for MCP-1/CCL2 in injury-induced inflammation revealed by in vitro, in silico, and clinical studies. PLoS One 2013; 8: e79804
    CrossrefPubMedSearch in Google Scholar
  • 20 Liu C, Zhao J, Liu Y. et al. A novel pentacyclic triterpenoid, Ilexgenin A, shows reduction of atherosclerosis in apolipoprotein E deficient mice. Int Immunopharmacol 2016; 40: 115-124
    CrossrefPubMedSearch in Google Scholar
  • 21 Klein K, Satler M, Elhenicky M. et al. Circulating levels of MCP-1 are increased in women with gestational diabetes. Prenat Diagn 2008; 28: 845-851
    CrossrefPubMedSearch in Google Scholar
  • 22 Telejko B, Kuzmicki M, Zonenberg A. et al. Circulating monocyte chemoattractant protein-1 in women with gestational diabetes. Folia Histochem Cytobiol 2007; 45: S153-S156
    PubMedSearch in Google Scholar
  • 23 Lu X, Wu F, Jiang M. et al. Curcumin ameliorates gestational diabetes in mice partly through activating AMPK. Pharmaceutical biology 2019; 57: 250-254
    CrossrefPubMedSearch in Google Scholar
  • 24 Seok SJ, Lee ES, Kim GT. et al. Blockade of CCL2/CCR2 signalling ameliorates diabetic nephropathy in db/db mice. Nephrol Dial Transplant 2013; 28: 1700-1710
    CrossrefPubMedSearch in Google Scholar
  • 25 Yu J, Zhou Y, Gui J. et al. Assessment of the number and function of macrophages in the placenta of gestational diabetes mellitus patients. J Huazhong Univ Sci Technolog Med Sci 2013; 33: 725-729
    CrossrefPubMedSearch in Google Scholar
  • 26 El-Bassyouni HT, Raouf SMA, Farag MK. et al. Dysregulation of tumor necrosis factor-a and interleukin-6 as predictors of gestational disorders. Middle East. J Med Genet 2018; 7: 112
    PubMedSearch in Google Scholar
  • 27 Siddiqui S, Waghdhare S, Goel C. et al. Augmentation of IL-6 production contributes to development of gestational diabetes mellitus: An Indian study. Diabetes Metab Syndr 2019; 13: 895-899
    CrossrefPubMedSearch in Google Scholar
  • 28 Agius E, Lacy KE, Vukmanovic-Stejic M. et al. Decreased TNF-alpha synthesis by macrophages restricts cutaneous immunosurveillance by memory CD4+T cells during aging. J Exp Med 2009; 206: 1929-1940
    CrossrefPubMedSearch in Google Scholar
  • 29 Gelen V, Şengül E, Atila G. et al. Association of gestational diabetes and proinflammatory cytokines (IL-6, TNF-a and IL-1b). J Embryol 2017; 1: 6
    PubMedSearch in Google Scholar
  • 30 Shi C, Pamer EG. Monocyte recruitment during infection and inflammation. Nat Rev Immunol 2011; 11: 762-774
    CrossrefPubMedSearch in Google Scholar
  • 31 Arango Duque G, Descoteaux A. Macrophage cytokines: Involvement in immunity and infectious diseases. Front Immunol 2014; 5: 491
    CrossrefPubMedSearch in Google Scholar