The relationship between KLF2/RelA imbalance and neutrophil apoptosis in asthmatic patients_Chinese Journal of Respiratory and Critical Care Medicine

Authors：

HUANG Jin ¹ ,  ZHU Liming ¹ , ZHU Yingqun ²

1. Elderly Respiratory Department, Hunan People’s Hospital, Changsha, Hunan 410016, P. R. China;
2. Third People's Hospital of Changsha, Hunan 410016, P. R. China;

Corresponding author：

ZHU Liming, Email: zhuliming3298@sina.com

Keywords：

Asthma; KLF2; RelA; Neutrophils; Apoptosis

DOI：

10.7507/1671-6205.201706029

Video：

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ObjectiveTo determine whether there is an imbalance of KLF2/RelA in peripheral blood neutrophils in patients with bronchial asthma, and explore the relationship between KLF2/RelA imbalance and neutrophil apoptosis.MethodsFrom April 2011 to April 2012, a total of 39 patients with acute attack of asthma in Hunan People's Hospital and Third People's Hospital of Changsha were enrolled, with 13 cases in mild asthma group, 17 cases in moderate asthma group, and 9 cases in severe asthma group. Fifteen healthy subjects were recruited as control group. Peripheral blood were collected from all subjects followed by separation of neutrophils. The apoptosis of neutrophils were measured by flow cytometry. The expression of KLF2 and RelA were detected by Western blot. The relationship between the ratio of KLF2/RelA and neutrophil apoptosis rate was analyzed by Pearson correlation test.ResultsNeutrophil apoptosis rates in the mild, moderate and severe asthma groups [(4.45±0.76)%, (2.10±0.25)%, (1.81±0.67)%, repectively] were lower than that in the healthy control group [(5.36±0.57)%, all P<0.01]. The apoptosis rates of neutrophils in the moderate and severe asthma groups were lower than that in the mild asthma group (bothP<0.01), but there was no significant difference between the moderate asthma group and the severe asthma group (P>0.05). The ratios of neutrophil KLF2/RelA in the mild, moderate and severe asthma groups were lower than that in the normal control group (0.667±0.351, 0.384±0.203, 0.536±0.293vs. 4.038±2.011, all P<0.01). There was no significant difference between the groups of mild, moderate and severe asthma (P>0.05). The neutrophil apoptosis rate was positively correlated with the percentage of neutrophil KLF2/RelA (r=0.592 0, P<0.000 1).ConclusionThere is an imbalance of KLF2/RelA in peripheral blood neutrophils in patients with bronchial asthma, and the imbalance of KLF2/RelA may be the mechanism of apoptosis of peripheral blood neutrophils.

Citation： HUANG Jin, ZHU Liming, ZHU Yingqun. The relationship between KLF2/RelA imbalance and neutrophil apoptosis in asthmatic patients. Chinese Journal of Respiratory and Critical Care Medicine, 2018, 17(1): 1-5. doi: 10.7507/1671-6205.201706029 Copy

1.	Gibson PG, Simpson JL, Saltos N. Heterogeneity of airway inflammation in persistent asthma : evidence of neutrophilic inflammation and increased sputum interleukin-8. Chest, 2001, 119(5): 1329-1336.
2.	Ordoñez CL, Shaughnessy TE, Matthay MA, et al. Increased neutrophil numbers and IL-8 levels in airway secretions in acute severe asthma. Am J Respir Crit Care Med, 2000, 161(4 Pt 1): 1185-1190.
3.	Parfrey H, Farahi N, Porter L, et al. Live and let die: is neutrophil apoptosis defective in severe asthma?. Thorax, 2010, 65(8): 665-667.
4.	Kuo CT, Veselits ML, Leiden JM. LKLF: a transcriptional regulator of single-positive T cell quiescence and survival. Science, 1997, 277(5334): 1986-1990.
5.	Nie FQ, Sun M, Yang JS, et al. Long noncoding RNA ANRIL promotes non-small cell lung cancer cell proliferation and inhibits apoptosis by silencing KLF2 and P21 expression. Mol Cancer Ther, 2015, 14(1): 268-277.
6.	Geering B, Simon HU. Peculiarities of cell death mechanisms in neutrophils. Cell Death Differ, 2011, 18(9): 1457-1569.
7.	Ward C, Chilvers ER, Lawson MF, et al. NF-kappaB activation is a critical regulator of human granulocyte apoptosis in vitro. J Biol Chem, 1999, 274(7): 4309-4318.
8.	Enenstein J, Milbauer L, Domingo E, et al. Proinflammatory phenotype with imbalance of KLF2 and RelA: risk of childhood stroke with sickle cell anemia. Am J Hematol, 2010, 85(1): 18-23.
9.	Woodruff PG, Khashayar R, Lazarus SC, et al. Relationship between airway inflammation, hyperresponsiveness, and obstruction in asthma. J Allergy Clin Immunol, 2001, 108(5): 753-758.
10.	Shaw DE, Berry MA, Hargadon B, et al. Association between neutrophilic airway inflammation and airflow limitation in adults with asthma. Chest, 2007, 132(6): 1871-1875.
11.	Anderson KP, Kern CB, Crable SC, et al. Isolation of a gene encoding a functional zinc finger protein homologous to erythroid Kruppel-like factor: identification of a new multigene family. Mol Cell Biol, 1995, 15(11): 5957-5965.
12.	Alberts-Grill N, Engelbertsen D, Bu D, et al. Dendritic Cell KLF2 Expression Regulates T Cell Activation and Proatherogenic Immune Responses. J Immunol, 2016, 197(12): 4651-4662.
13.	Rabacal W, Pabbisetty SK, Hoek KL, et al. Transcription factor KLF2 regulates homeostatic NK cell proliferation and survival. Proc Natl Acad Sci U S A, 2016, 113(19): 5370-5375.
14.	Lee JY, Skon CN, Lee YJ, et al. The transcription factor KLF2 restrains CD4? T follicular helper cell differentiation. Immunity, 2015, 42(2): 252-264.
15.	Hart GT, Wang X, Hogquist KA, et al. Krüppel-like factor 2 (KLF2) regulates B-cell reactivity, subset differentiation, and trafficking molecule expression. Proc Natl Acad Sci U S A, 2011, 108(2): 716-721.
16.	Komaravolu RK, Adam C, Moonen JR, et al. Erk5 inhibits endothelial migration via KLF2-dependent down-regulation of PAK1. Cardiovasc Res, 2015, 105(1): 86-95.
17.	Carlson CM, Endrizzi BT, Wu J, et al. Kruppel-like factor 2 regulates thymocyte and T-cell migration. Nature, 2006, 442(7100): 299-302.
18.	Sheppard KA, Rose DW, Haque ZK, et al. Transcriptional activation by NF-kappaB requires multiple coactivators. Mol Cell Biol, 1999, 19(9): 6367-6678.
19.	Buckley AF, Kuo CT, Leiden JM. Transcription factor LKLF is sufficient to program T cell quiescence via a c-Myc--dependent pathway. Nat Immunol, 2001, 2(8): 698-704.
20.	Bista P, Mele DA, Baez DV, et al. Lymphocyte quiescence factor Dpp2 is transcriptionally activated by KLF2 and TOB1. Mol Immunol, 2008, 45(13): 3618-3623.

1. Gibson PG, Simpson JL, Saltos N. Heterogeneity of airway inflammation in persistent asthma : evidence of neutrophilic inflammation and increased sputum interleukin-8. Chest, 2001, 119(5): 1329-1336.
2. Ordoñez CL, Shaughnessy TE, Matthay MA, et al. Increased neutrophil numbers and IL-8 levels in airway secretions in acute severe asthma. Am J Respir Crit Care Med, 2000, 161(4 Pt 1): 1185-1190.
3. Parfrey H, Farahi N, Porter L, et al. Live and let die: is neutrophil apoptosis defective in severe asthma?. Thorax, 2010, 65(8): 665-667.
4. Kuo CT, Veselits ML, Leiden JM. LKLF: a transcriptional regulator of single-positive T cell quiescence and survival. Science, 1997, 277(5334): 1986-1990.
5. Nie FQ, Sun M, Yang JS, et al. Long noncoding RNA ANRIL promotes non-small cell lung cancer cell proliferation and inhibits apoptosis by silencing KLF2 and P21 expression. Mol Cancer Ther, 2015, 14(1): 268-277.
6. Geering B, Simon HU. Peculiarities of cell death mechanisms in neutrophils. Cell Death Differ, 2011, 18(9): 1457-1569.
7. Ward C, Chilvers ER, Lawson MF, et al. NF-kappaB activation is a critical regulator of human granulocyte apoptosis in vitro. J Biol Chem, 1999, 274(7): 4309-4318.
8. Enenstein J, Milbauer L, Domingo E, et al. Proinflammatory phenotype with imbalance of KLF2 and RelA: risk of childhood stroke with sickle cell anemia. Am J Hematol, 2010, 85(1): 18-23.
9. Woodruff PG, Khashayar R, Lazarus SC, et al. Relationship between airway inflammation, hyperresponsiveness, and obstruction in asthma. J Allergy Clin Immunol, 2001, 108(5): 753-758.
10. Shaw DE, Berry MA, Hargadon B, et al. Association between neutrophilic airway inflammation and airflow limitation in adults with asthma. Chest, 2007, 132(6): 1871-1875.
11. Anderson KP, Kern CB, Crable SC, et al. Isolation of a gene encoding a functional zinc finger protein homologous to erythroid Kruppel-like factor: identification of a new multigene family. Mol Cell Biol, 1995, 15(11): 5957-5965.
12. Alberts-Grill N, Engelbertsen D, Bu D, et al. Dendritic Cell KLF2 Expression Regulates T Cell Activation and Proatherogenic Immune Responses. J Immunol, 2016, 197(12): 4651-4662.
13. Rabacal W, Pabbisetty SK, Hoek KL, et al. Transcription factor KLF2 regulates homeostatic NK cell proliferation and survival. Proc Natl Acad Sci U S A, 2016, 113(19): 5370-5375.
14. Lee JY, Skon CN, Lee YJ, et al. The transcription factor KLF2 restrains CD4? T follicular helper cell differentiation. Immunity, 2015, 42(2): 252-264.
15. Hart GT, Wang X, Hogquist KA, et al. Krüppel-like factor 2 (KLF2) regulates B-cell reactivity, subset differentiation, and trafficking molecule expression. Proc Natl Acad Sci U S A, 2011, 108(2): 716-721.
16. Komaravolu RK, Adam C, Moonen JR, et al. Erk5 inhibits endothelial migration via KLF2-dependent down-regulation of PAK1. Cardiovasc Res, 2015, 105(1): 86-95.
17. Carlson CM, Endrizzi BT, Wu J, et al. Kruppel-like factor 2 regulates thymocyte and T-cell migration. Nature, 2006, 442(7100): 299-302.
18. Sheppard KA, Rose DW, Haque ZK, et al. Transcriptional activation by NF-kappaB requires multiple coactivators. Mol Cell Biol, 1999, 19(9): 6367-6678.
19. Buckley AF, Kuo CT, Leiden JM. Transcription factor LKLF is sufficient to program T cell quiescence via a c-Myc--dependent pathway. Nat Immunol, 2001, 2(8): 698-704.
20. Bista P, Mele DA, Baez DV, et al. Lymphocyte quiescence factor Dpp2 is transcriptionally activated by KLF2 and TOB1. Mol Immunol, 2008, 45(13): 3618-3623.

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