Increased, recruitment of inflammatory cells

CL:0009002

CL inflammatory cell

CL:0000235

CL macrophage

GO:0006954

GO inflammatory response

GO:0042116

GO macrophage activation

WIKI increased

WCS_9606

common toxicological species human

10090

NCBI mouse

10116

NCBI rats

10090

NCBI Mus musculus

9606

NCBI Homo sapiens

Increased, recruitment of inflammatory cells

Recruitment of inflammatory cells

Tissue

Pro-inflammatory cells originate in bone marrow and are recruited to the site of infection or injury via circulation following specific pro-inflammatory mediator (cytokine and chemokine) signalling. Pro-inflammatory cells are recruited to lungs to clear the invading pathogen or the toxic substance. Monocytes (dendritic cells, macrophages, and neutrophils) are subsets of circulating white blood cells that are involved in the immune responses to pathogen or toxicant stimuli (Kolaczkowska and Kubes, 2013; Kopf et al., 2015). They are derived from the bone marrow. They can differentiate into different macrophage types and dendritic cells. They can be categorised based on their size, the type of cell surface receptors and their ability to differentiate following external or internal stimulus such as increased expression of cytokines. Monocytes participate in tissue healing, clearance of toxic substance or pathogens, and in the initiation of adaptive immunity. Recruited monocytes can also influence pathogenesis (Ingersoll et al., 2011). Sensing or recognition of pathogens and harmful substances results in the recruitment of monocytes to lungs (Shi and Pamer, 2011). Activated immune cells secrete a variety of pro-inflammatory mediators, the purpose of which is to propagate the immune signalling and response, which when not controlled, leads to chronic inflammation, cell death and tissue injury. Thus, Event 1496 and Event 1497 act in a positive feedback loop mechanism and propagate the proinflammatory environment. Literature evidence for its perturbation: Macrophages accumulate in bronchoalveolar fluid (BALF) post-exposure to bleomycin (Phan et al., 1980; Smith et al., 1995). Nanomaterial (NM)-induced inflammation is predominantly neutrophilic (Poulsen et al., 2015; Rahman L et al., 2017a; Rahman et al., 2017b; Shvedova et al., 2005). An increased number of neutrophils (Reynolds et al., 1977) is observed in the BALF of patients with idiopathic pulmonary fibrosis. Eosinophils are a type of white blood cells and a type of granulocytes (contain granules and enzymes) that are recruited following exposure to allergens, during allergic reactions such as asthma or during fibrosis (Reynolds et al., 1977). Multi-walled carbon nanotubes (MWCNTs) induce increased eosinophil count in lungs (Købler C et al., 2015). MWCNTs act as allergens and induce lung infiltration of eosinophils and cause airway hypersensitivity (Beamer et al., 2013). It is important to note that the stressor-induced Event 1495, Event 1496, and Event 1497 are part of the functional changes that we collectively consider as inflammation, and together, they mark the initiation of acute inflammatory phase. Event 1495 and Event 1496 occur at the cellular level. Event 1497 occurs at the tissue level.

In vivo, recruitment of pro-inflammatory cells is measured using BALF cellularity assay. The fluid lining the lung epithelium is lavaged (BALF) and its composition is assessed as marker of lung immune response to the toxic substances or pathogens. BALF is assessed quantitatively for types of infiltrating cells, levels and types of cytokines and chemokines. Thus, BALF assessment can aid in developing dose-response of a substance, to rank a substances’ potency and to set up no effect level of exposure for the regulatory decision making. For NMs, in vivo BALF assessment is recommended as a mandatory test (discussed in ENV/JM/MONO(2012)40 and also in OECD inhalation test guideline for NMs). Temporal changes in the BALF composition can be prognostic of initiation and progression of lung immune disease (Cho et al., 2010). In vitro, it is difficult to assess the recruitment of pro-inflammatory cells. Thus, a suit of pro-inflammatory mediators specific to cell types are assessed using the same techniques mentioned above (real-time reverse transcription-polymerase chain reaction [qRT-PCR], enzyme-linked immunosorbent assays [ELISA], immunohistochemistry) in cell culture models, as indicative of recruitment of cells into the lungs. Alternatively, the use of precision cut lung slices can allow for limited assessment of recruitment of tissue resident inflammatory cells, based on the repertoire of cells remaining in the specific slice following harvesting. This method was used to show that there is a histological increase in inflammatory foci following treatment with bleomycin and MWCNTs (Rahman et al., 2020). Finally, more complicated microfluidic lung-on-a-chip devices can be used to assess the migration of select immune cells and fibroblasts toward a simulated epithelium following treatment with a pro-fibrotic compound (He et al., 2017). However, this method is limited to two cell types, and it lacks the reservoirs of immune cells present in the body in vivo.

Human, mouse, rat

High Mixed

High

All life stages

High High High

1. Beamer CA, Girtsman TA, Seaver BP, Finsaas KJ, Migliaccio CT, Perry VK, Rottman JB, Smith DE, Holian A. IL-33 mediates multi-walled carbon nanotube (MWCNT)-induced airway hyper-reactivity via the mobilization of innate helper cells in the lung. Nanotoxicology. 2013 Sep;7(6):1070-81. doi: 10.3109/17435390.2012.702230. 2. Cho WS, Duffin R, Poland CA, Howie SE, MacNee W, Bradley M, Megson IL, Donaldson K. Metal oxide nanoparticles induce unique inflammatory footprints in the lung: important implications for nanoparticle testing. Environ Health Perspect. 2010 Dec;118(12):1699-706. doi: 10.1289/ehp.1002201.  3. He J, Chen W, Deng S, Xie L, Feng J, Geng J, et al. Modeling alveolar injury using microfluidic co-cultures for monitoring bleomycin-induced epithelial/fibroblastic cross-talk disorder. RSC Advances. 2017 7(68):42738-49. doi: 10.1039/C7RA06752F. 4. Ingersoll MA, Platt AM, Potteaux S, Randolph GJ. Monocyte trafficking in acute and chronic inflammation. Trends Immunol. 2011 Oct;32(10):470-7. doi: 10.1016/j.it.2011.05.001. 5. Købler C, Poulsen SS, Saber AT, Jacobsen NR, Wallin H, Yauk CL, Halappanavar S, Vogel U, Qvortrup K, Mølhave K. Time-dependent subcellular distribution and effects of carbon nanotubes in lungs of mice. PLoS One. 2015 Jan 23;10(1):e0116481. doi: 10.1371/journal.pone.0116481.  6. Kolaczkowska E, Kubes P. Neutrophil recruitment and function in health and inflammation. Nat Rev Immunol. 2013 Mar;13(3):159-75. doi: 10.1038/nri3399.  7. Kopf M, Schneider C, Nobs SP. The development and function of lung-resident macrophages and dendritic cells. Nat Immunol. 2015 Jan;16(1):36-44. doi: 10.1038/ni.3052. 8. Phan SH, Thrall RS, Ward PA. Bleomycin-induced pulmonary fibrosis in rats: biochemical demonstration of increased rate of collagen synthesis. Am Rev Respir Dis. 1980 Mar;121(3):501-6. doi: 10.1164/arrd.1980.121.3.501.  9. Poulsen SS, Saber AT, Williams A, Andersen O, Købler C, Atluri R, Pozzebon ME, Mucelli SP, Simion M, Rickerby D, Mortensen A, Jackson P, Kyjovska ZO, Mølhave K, Jacobsen NR, Jensen KA, Yauk CL, Wallin H, Halappanavar S, Vogel U. MWCNTs of different physicochemical properties cause similar inflammatory responses, but differences in transcriptional and histological markers of fibrosis in mouse lungs. Toxicol Appl Pharmacol. 2015 Apr 1;284(1):16-32. doi: 10.1016/j.taap.2014.12.011.  10. Rahman L, Wu D, Johnston M, William A, Halappanavar S. Toxicogenomics analysis of mouse lung responses following exposure to titanium dioxide nanomaterials reveal their disease potential at high doses. Mutagenesis. 2017a Jan;32(1):59-76. doi: 10.1093/mutage/gew048.  11. Rahman L, Jacobsen NR, Aziz SA, Wu D, Williams A, Yauk CL, White P, Wallin H, Vogel U, Halappanavar S. Multi-walled carbon nanotube-induced genotoxic, inflammatory and pro-fibrotic responses in mice: Investigating the mechanisms of pulmonary carcinogenesis. Mutat Res Genet Toxicol Environ Mutagen. 2017b Nov;823:28-44. doi: 10.1016/j.mrgentox.2017.08.005.  12. Rahman L, Williams A, Gelda K, Nikota J, Wu D, Vogel U, Halappanavar S. 21st Century Tools for Nanotoxicology: Transcriptomic Biomarker Panel and Precision-Cut Lung Slice Organ Mimic System for the Assessment of Nanomaterial-Induced Lung Fibrosis. Small. 2020 Sep;16(36):e2000272. doi: 10.1002/smll.202000272.  13. Reynolds HY, Fulmer JD, Kazmierowski JA, Roberts WC, Frank MM, Crystal RG. Analysis of cellular and protein content of broncho-alveolar lavage fluid from patients with idiopathic pulmonary fibrosis and chronic hypersensitivity pneumonitis. J Clin Invest. 1977 Jan;59(1):165-75. doi: 10.1172/JCI108615. 14. Shi C, Pamer EG. Monocyte recruitment during infection and inflammation. Nat Rev Immunol. 2011 Oct 10;11(11):762-74. doi: 10.1038/nri3070.  15. Shvedova AA, Kisin ER, Mercer R, Murray AR, Johnson VJ, Potapovich AI, Tyurina YY, Gorelik O, Arepalli S, Schwegler-Berry D, Hubbs AF, Antonini J, Evans DE, Ku BK, Ramsey D, Maynard A, Kagan VE, Castranova V, Baron P. Unusual inflammatory and fibrogenic pulmonary responses to single-walled carbon nanotubes in mice. Am J Physiol Lung Cell Mol Physiol. 2005 Nov;289(5):L698-708. doi: 10.1152/ajplung.00084.2005.   16. Smith RE, Strieter RM, Zhang K, Phan SH, Standiford TJ, Lukacs NW, Kunkel SL. A role for C-C chemokines in fibrotic lung disease. J Leukoc Biol. 1995 May;57(5):782-7. doi: 10.1002/jlb.57.5.782.  AOPWiki 2018-01-03T09:31:07

2023-05-12T17:03:00

Insulin resistance

Cellular

AOPWiki 2022-06-27T23:17:28

2022-06-27T23:17:28

Increased adipocyte size

Cellular

AOPWiki 2023-04-05T05:50:28

2023-04-05T05:50:28

Increased adipocyte numbers

Cellular

AOPWiki 2023-04-05T05:51:00

2023-04-05T05:51:00

Metabolically unhealthy Obesity

Individual

AOPWiki 2023-04-05T05:55:29

2023-04-05T05:55:29

Increased fat mass

Organ

AOPWiki 2023-04-05T05:34:31

2023-04-05T05:34:31

Estrogen receptor alpha inactivation

ERa inactivation

Molecular

AOPWiki 2023-04-05T05:36:56

2023-04-10T13:29:15

increased lipid accumulation

Cellular

AOPWiki 2023-04-05T07:06:54

2023-04-05T07:06:54

Increased pro-inflammatory cytokine expression

Increased cytokine expression

Cellular

AOPWiki 2023-04-06T10:15:14

2023-04-06T10:15:14

Increase in inflammation

Tissue

AOPWiki 2019-05-03T14:27:00

2019-05-03T14:27:00

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ERa inactivation alters AT expansion and functions and leads to insulin resistance and metabolically unhealthy obesity

ERa inactivation leads to increased fat mass and insulin resistance.

Evgeniia Kazymova

Min Ji Kim1, Etienne Blanc2, Jean Pascal De Bandt2, Antoine Girardon2, Xavier Coumoul2, Karine Audouze2 1. Université Sorbonne Paris Nord, Inserm 1124, Paris, France 2. Université Paris Cité, Inserm 1124, Paris, France

2.5

Estrogens are not only important in the development and the functions of reproductive system, but they also play a crucial role in adipose tissue distribution and insulin sensitivity and these effects mainly seem to be mediated by one of their receptors, ERa (estrogen receptor alpha). Indeed, ERa KO, but not ERb KO mice show an increased fat mass and insulin resistance phenotype in both sexes [1–3]. ERa deletion also leads to adipose tissue inflammation with an increased expression of pro-inflammatory cytokines and impaired insulin signaling in adipose tissue leading to insulin resistance [3]. An increased adiposity, an increased inflammation and an increased risk of obesity-related metabolic disorders such as insulin resistance, type 2 diabetes and cardiovascular disease can also be encountered in ovariectomized female mice or in postmenopausal women and weight gain or metabolic disorders are improved by E2 treatment or hormone therapy [4–7]. Furthermore, higher insulin resistance and/or adiposity were observed in men [8] and in postmenopausal women treated with aromatase inhibitors [9]. Aromatase-deficient mice, a model of estrogen insufficiency, also display an increased adiposity that is reversed by estrogen replacement [10]. An increased fat mass, inflammation and insulin resistance are hallmarks of the metabolic syndrome but there is no AOP considering the “increased adipocyte numbers” or “size” or “increased lipid accumulation” that lead to the “increased fat mass”. Furthermore, if the “recruitment of inflammatory cells” is an existing KE (1497) in AOP wiki, “increased pro-inflammatory cytokine expression”, that is commonly measured in experimental laboratories is missing. These events are well-known factor linking obesity and insulin resistance (KE 2018) leading to metabolically unhealthy obesity [11,12]. Thus, we propose an AOP linking ESR1 inactivation to the hallmarks of the metabolic syndrome because impairment of estrogen synthesis and of ERa signaling that can lead to the events must be considered to decipher mechanisms of action leading to the metabolic syndrome.

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High

High Female High Male High High

<div> <table class="table table-bordered table-fullwidth"> <thead> <tr> <th>Modulating Factor (MF)</th> <th>Influence or Outcome</th> <th>KER(s) involved</th> </tr> </thead> <tbody> <tr> <td> </td> <td> </td> <td> </td> </tr> </tbody> </table> </div>

[1]       P.A. Heine, J.A. Taylor, G.A. Iwamoto, D.B. Lubahn, P.S. Cooke, Increased adipose tissue in male and female estrogen receptor-alpha knockout mice, Proc Natl Acad Sci U S A. 97 (2000) 12729–12734. https://doi.org/10.1073/pnas.97.23.12729. [2]       C. Ohlsson, N. Hellberg, P. Parini, O. Vidal, M. Bohlooly-Y, M. Rudling, M.K. Lindberg, M. Warner, B. Angelin, J.A. Gustafsson, Obesity and disturbed lipoprotein profile in estrogen receptor-alpha-deficient male mice, Biochem Biophys Res Commun. 278 (2000) 640–645. https://doi.org/10.1006/bbrc.2000.3827. [3]       V. Ribas, M.T.A. Nguyen, D.C. Henstridge, A.-K. Nguyen, S.W. Beaven, M.J. Watt, A.L. Hevener, Impaired oxidative metabolism and inflammation are associated with insulin resistance in ERalpha-deficient mice, Am J Physiol Endocrinol Metab. 298 (2010) E304-319. https://doi.org/10.1152/ajpendo.00504.2009. [4]       N. Geary, L. Asarian, K.S. Korach, D.W. Pfaff, S. Ogawa, Deficits in E2-dependent control of feeding, weight gain, and cholecystokinin satiation in ER-alpha null mice, Endocrinology. 142 (2001) 4751–4757. https://doi.org/10.1210/endo.142.11.8504. [5]       L.B. Jensen, P. Vestergaard, A.P. Hermann, J. Gram, P. Eiken, B. Abrahamsen, C. Brot, N. Kolthoff, O.H. Sørensen, H. Beck-Nielsen, S.P. Nielsen, P. Charles, L. Mosekilde, Hormone replacement therapy dissociates fat mass and bone mass, and tends to reduce weight gain in early postmenopausal women: a randomized controlled 5-year clinical trial of the Danish Osteoporosis Prevention Study, J Bone Miner Res. 18 (2003) 333–342. https://doi.org/10.1359/jbmr.2003.18.2.333. [6]       K.L. Margolis, D.E. Bonds, R.J. Rodabough, L. Tinker, L.S. Phillips, C. Allen, T. Bassford, G. Burke, J. Torrens, B.V. Howard, Women’s Health Initiative Investigators, Effect of oestrogen plus progestin on the incidence of diabetes in postmenopausal women: results from the Women’s Health Initiative Hormone Trial, Diabetologia. 47 (2004) 1175–1187. https://doi.org/10.1007/s00125-004-1448-x. [7]       N.H. Rogers, J.W. Perfield, K.J. Strissel, M.S. Obin, A.S. Greenberg, Reduced energy expenditure and increased inflammation are early events in the development of ovariectomy-induced obesity, Endocrinology. 150 (2009) 2161–2168. https://doi.org/10.1210/en.2008-1405. [8]       F.W. Gibb, N.Z.M. Homer, A.M.M. Faqehi, R. Upreti, D.E. Livingstone, K.J. McInnes, R. Andrew, B.R. Walker, Aromatase Inhibition Reduces Insulin Sensitivity in Healthy Men, J Clin Endocrinol Metab. 101 (2016) 2040–2046. https://doi.org/10.1210/jc.2015-4146. [9]       F.W. Gibb, J.M. Dixon, C. Clarke, N.Z. Homer, A.M.M. Faqehi, R. Andrew, B.R. Walker, Higher Insulin Resistance and Adiposity in Postmenopausal Women With Breast Cancer Treated With Aromatase Inhibitors, J Clin Endocrinol Metab. 104 (2019) 3670–3678. https://doi.org/10.1210/jc.2018-02339. [10]     M.E. Jones, A.W. Thorburn, K.L. Britt, K.N. Hewitt, N.G. Wreford, J. Proietto, O.K. Oz, B.J. Leury, K.M. Robertson, S. Yao, E.R. Simpson, Aromatase-deficient (ArKO) mice have a phenotype of increased adiposity, Proc Natl Acad Sci U S A. 97 (2000) 12735–12740. https://doi.org/10.1073/pnas.97.23.12735. [11]     M. Longo, F. Zatterale, J. Naderi, L. Parrillo, P. Formisano, G.A. Raciti, F. Beguinot, C. Miele, Adipose Tissue Dysfunction as Determinant of Obesity-Associated Metabolic Complications, Int J Mol Sci. 20 (2019) 2358. https://doi.org/10.3390/ijms20092358. [12]     A.R. Saltiel, J.M. Olefsky, Inflammatory mechanisms linking obesity and metabolic disease, J Clin Invest. 127 (2017) 1–4. https://doi.org/10.1172/JCI92035. AOPWiki 2023-04-05T05:11:25

2023-09-25T16:27:14