Knockdown of KLK13 has a protective effect against ovalbumin-induced asthma in mice
Main Article Content
Keywords
airway inflammation, airway remodeling, asthma, KLK13, NF-κB, oxidative stress
Abstract
Background: Asthma remains a critical global health concern impacting diverse age groups, with incidence rates rising continuously. Recent studies have identified elevated levels of kallikrein-related peptidase 13 (KLK13) in nasal lavage specimens of asthma patients; however, its functional mechanisms remain explored.
Methods: An experimental asthma model was established in mice through ovalbumin (OVA) sensitization with an Al(OH)3 adjuvant. The role of KLK13 was evaluated using immunohistochemistry, hematoxylin–eosin, and Masson trichrome staining, pulmonary function testing, enzyme-linked immunosorbent serological assay (ELISA), biochemical measurements, and immunoblotting.
Results: OVA-challenged mice exhibited marked upregulation of KLK13 expression. Genetic silencing of KLK13 reduced airway hyperresponsiveness in the asthma model. Histological analysis showed that OVA exposure caused extensive peribronchial inflammatory cell infiltration, bronchial wall thickening with luminal narrowing, and pulmonary collagen accumulation, all of which were significantly improved by KLK13 knockdown. OVA administration also induced substantial increases in interleukin (IL)-4, IL-5, IL-13, and immunoglobulin E, while KLK13 silencing significantly attenuated these elevations. Biochemical assays revealed increased malonaldehyde content and reactive oxygen species generation, alongside decreased superoxide dismutase activity and glutathione peroxidase levels in OVA-exposed mice; these changes were effectively normalized by KLK13 knockdown. At the molecular level, KLK13 inhibition reduced phosphorylation of inhibitor of nuclear factor-κB (NF-κB) alpha and p65 subunits, thereby suppressing activation of NF-κB pathway in OVA-induced asthma.
Conclusion: KLK13 depletion ameliorates asthmatic pathology by reducing airway inflammation, preventing structural remodeling, and restoring redox balance, primarily through NF-κB signaling modulation.
References
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6 Bacharier LB, Jackson DJ. Biologics in the treatment of asthma in children and adolescents. J Allergy Clin Immunol. 2023;151(3):581–89. 10.1016/j.jaci.2023.01.002
7 Wirthgen E, Quickert S, Weitzel J, Salewski B, Ballmann M. Safety of biologics for the treatment of asthma in children and adolescents: A systematic review. Eur Respir Rev. 2025;34(176):240269. 10.1183/16000617.0269-2024
8 Lenga Ma Bonda W, Iochmann S, Magnen M, Courty Y, Reverdiau P. Kallikrein-related peptidases in lung diseases. Biol Chem. 2018;399(9):959–71. 10.1515/hsz-2018-0114
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12 Gueugnon F, Barascu A, Mavridis K, Petit-Courty A, Marchand-Adam S, Gissot V, et al. Kallikrein-related peptidase 13: An independent indicator of favorable prognosis for patients with nonsmall cell lung cancer. Tumour Biol. 2015;36(7):4979–86. 10.1007/s13277-015-3148-1
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16 National Research Council Committee for the Update of the Guide for the Care and Use of Laboratory Animals. Guide for the Care and Use of Laboratory Animals. Washington, DC: National Academies of Sciences Press (US), 2011. PMid: 21595115.
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21 Zhang N, Lu HT, Zhang RJ, Sun XJ. Protective effects of methane-rich saline on mice with allergic asthma by inhibiting inflammatory response, oxidative stress and apoptosis. J Zhejiang Univ Sci B. 2019;20(10):828–37. 10.1631/jzus.B1900195
22 Wang Z, Zhang H, Sun X, Ren L. The protective role of vitamin D3 in a murine model of asthma via the suppression of TGF-β/Smad signaling and activation of the Nrf2/HO-1 pathway. Mol Med Rep. 2016;14(3):2389–96. 10.3892/mmr.2016.5563
23 Padra M, Bergwik J, Adler A, Marcoux G, Bhongir RKV, Papareddy P, et al. Tartrate-resistant acid phosphatase 5 (TRAP5) promotes eosinophil migration during allergic asthma. Am J Respir Cell Mol Biol. 2025;73(4):612–22. 10.1165/rcmb.2024-0304OC
24 Lee CC, Chen CH, Kenyon NJ, Wang CN, Tsai HC, Chiu CL, et al. Inhibition of MARCKS phosphorylation attenuates of dendritic cell migration in a murine model of acute asthma. Eur J Pharmacol. 2024;176867. 10.1016/j.ejphar.2024.176867
25 Gon Y, Hashimoto S. Role of airway epithelial barrier dysfunction in pathogenesis of asthma. Allergol Int. 2018;67(1):12–7. 10.1016/j.alit.2017.08.011
26 Chen YF, Huang G, Wang YM, Cheng M, Zhu FF, Zhong JN, et al. Exchange protein directly activated by cAMP (Epac) protects against airway inflammation and airway remodeling in asthmatic mice. Respir Res. 2019;20(1):285. 10.1186/s12931-019-1260-2
27 Lenga Ma Bonda W, Lavergne M, Vasseur V, Brisson L, Roger S, Legras A, et al. Kallikrein-related peptidase 5 contributes to the remodeling and repair of bronchial epithelium. Faseb J. 2021;35(10):e21838. 10.1096/fj.202002649R
28 Willis-Owen SAG, Cookson WOC, Moffatt MF. The genetics and genomics of asthma. Annu Rev Genomics Hum Genet. 2018;19:223–46. 10.1146/annurev-genom-083117-021651
29 Lambrecht BN, Hammad H, Fahy JV. The cytokines of asthma. Immunity. 2019;50(4):975–91. 10.1016/j.immuni.2019.03.018
30 Pritam P, Manna S, Sahu A, Swain SS, Ramchandani S, Bissoyi S, et al. Eosinophil: A central player in modulating pathological complexity in asthma. Allergol Immunopathol (Madr). 2021;49(2):191–207. 10.15586/aei.v49i2.50
31 Kidd P. Th1/Th2 balance: The hypothesis, its limitations, and implications for health and disease. Altern Med Rev. 2003;8(3):223–46.
32 Steinke JW, Borish L. Th2 cytokines and asthma. Interleukin-4: Its role in the pathogenesis of asthma, and targeting it for asthma treatment with interleukin-4 receptor antagonists. Respir Res. 2001;2(2):66–70. 10.1186/rr40
33 Foster PS, Hogan SP, Ramsay AJ, Matthaei KI, Young IG. Interleukin 5 deficiency abolishes eosinophilia, airways hyperreactivity, and lung damage in a mouse asthma model. J Exp Med. 1996;183(1):195–201. 10.1084/jem.183.1.195
34 Wills-Karp M, Luyimbazi J, Xu X, Schofield B, Neben TY, Karp CL, et al. Interleukin-13: Central mediator of allergic asthma. Science. 1998;282(5397):2258–61. 10.1126/science.282.5397.2258
35 Truyen E, Coteur L, Dilissen E, Overbergh L, Dupont LJ, Ceuppens JL, et al. Evaluation of airway inflammation by quantitative Th1/Th2 cytokine mRNA measurement in sputum of asthma patients. Thorax. 2006;61(3):202–8. 10.1136/thx.2005.052399
36 Ezzat DA, Morgan DS, Mohamed RA, Mohamed AF. Genetic association of interleukin 18 (-607C/A, rs1946518) single nucleotide polymorphism with asthmatic children, disease severity and total IgE serum level. Cent Eur J Immunol. 2019;44(3):285–91. 10.5114/ceji.2019.89603
37 Shao Y, Zhou Q, Xue J, Shen B, Ji J, Wei Z. Melatonin ameliorates cisplatin-induced asthenozoospermia via reducing oxidative stress. J Mens Health (JOMH). 2022;18(1):16. 10.31083/jomh.2021.127
38 Ma X, Dong J, Wang Y, Zhang P. Protopine regulates oxidative stress, apoptosis and autophagy in H9C2 cardiomyocytes under hypoxic conditions. Signa Vitae. 2024;20(10):113–20. 10.22514/sv.2024.132
39 Zhang L, Zhang Y. Moscatilin inhibits sevoflurane-induced inflammatory and oxidative stress injury in hippocampal neuronal HT22 cells. Signa Vitae. 2024;20(6):67–73. 10.22514/sv.2024.073
40 Pan D, Ye H, Wang J, Mao J. Gentianine facilitates proliferation and inhibits inflammation and oxidative stress in caerulein-triggered acute pancreatitis cell model. Signa Vitae. 2024;20(5):77–84.
41 Zhang C, Xie M, Wang Y, Han T. Tussilagone inhibits inflammation and oxidative stress to alleviate acute pancreatitis. Signa Vitae. 2024;20(1):133–39.
42 Al-Afaleg NO, Al-Senaidy A, El-Ansary A. Oxidative stress and antioxidant status in Saudi asthmatic patients. Clin Biochem. 2011;44(8–9):612–7. 10.1016/j.clinbiochem.2011.01.016
43 Michaeloudes C, Abubakar-Waziri H, Lakhdar R, Raby K, Dixey P, Adcock IM, et al. Molecular mechanisms of oxidative stress in asthma. Mol Aspects Med. 2022;85:101026. 10.1016/j.mam.2021.101026
44 Gwarzo MY, Muhammad SA. Extracellular superoxide dismutase activity and plasma malondialdehyde in human immunodeficiency virus subjects of Kano state as surrogate markers of CD4 status. Int J Biomed Sci. 2010;6(4):294–300. 10.59566/IJBS.2010.6294
45 Jin Y, Huang J, Ma N. In vitro effects of ganoderic acid A on NF-κB-mediated inflammatory response in caerulein-stimulated pancreatic acinar cells. Signa Vitae. 2024;20(6):93–8. 10.22514/sv.2024.075
46 Pan D, Rao X, Gong M, Zhou J. Polygonatum cyrtonema Hua polysaccharides regulates NF-κB and Nrf2 pathways to alleviates oxidative stress and neuroinflammation in cerebral ischemia/reperfusion injury. Signa Vitae. 2024;20(12):108–15. 10.22514/sv.2024.162
47 Mathes E, O’Dea EL, Hoffmann A, Ghosh G. NF-kappa B dictates the degradation pathway of Ikappa B alpha. Embo J. 2008;27(9):1357–67. 10.1038/emboj.2008.73
48 Liu T, Zhang L, Joo D, Sun SC. NF-κB signaling in inflammation. Signal Transduct Target Ther. 2017;2:17023. 10.1038/sigtrans.2017.23
49 Trejo Bittar HE, Yousem SA, Wenzel SE. Pathobiology of severe asthma. Annu Rev Pathol. 2015;10:511–45. 10.1146/annurev-pathol-012414-040343
50 Dong J, Liao W, Peh HY, Chan TK, Tan WS, Li L, et al. Ribosomal protein S3 gene silencing protects against experimental allergic asthma. Br J Pharmacol. 2017;174(7):540–52. 10.1111/bph.13717
51 Gu X, Zhang Q, Du Q, Shen H, Zhu Z. Pinocembrin attenuates allergic airway inflammation via inhibition of NF-κB pathway in mice. Int Immunopharmacol. 2017;53:90–5. 10.1016/j.intimp.2017.10.005
2 Global Initiative for Asthma. Global strategy for asthma management and prevention, 2025 [internet]. [cited May 2025]. Available from: www.ginasthma.org.
3 Zhang B, Li ZF, An ZY, Zhang L, Wang JY, Hao MD, et al. Association between asthma and all-cause mortality and cardiovascular disease morbidity and mortality: A meta-analysis of cohort studies. Front Cardiovasc Med. 2022;9:861798. 10.3389/fcvm.2022.861798
4 Naqvi H, Searles CD. Association between asthma and cardiovascular disease among a United States representative population. Int J Cardiol Cardiovasc Risk Prev. 2025;26:200451. 10.1016/j.ijcrp.2025.200451
5 Jinghua S, Gaonian Z, Su J. Relationship between allergic asthma and cerebrovascular accident: Allergic asthma can increase recurrence of stroke. Postepy Dermatol Alergol. 2025;42(2):150–55. 10.5114/ada.2024.145458
6 Bacharier LB, Jackson DJ. Biologics in the treatment of asthma in children and adolescents. J Allergy Clin Immunol. 2023;151(3):581–89. 10.1016/j.jaci.2023.01.002
7 Wirthgen E, Quickert S, Weitzel J, Salewski B, Ballmann M. Safety of biologics for the treatment of asthma in children and adolescents: A systematic review. Eur Respir Rev. 2025;34(176):240269. 10.1183/16000617.0269-2024
8 Lenga Ma Bonda W, Iochmann S, Magnen M, Courty Y, Reverdiau P. Kallikrein-related peptidases in lung diseases. Biol Chem. 2018;399(9):959–71. 10.1515/hsz-2018-0114
9 Yousef GM, Chang A, Diamandis EP. Identification and characterization of KLK-L4, a new Kallikrein-like gene that appears to be downregulated in breast cancer tissues. J Biol Chem. 2000;275(16):11891–98. 10.1074/jbc.275.16.11891
10 Sumiya R, Yamada K, Hagiwara T, Nagasaka S, Miyazaki H, Igari T, et al. Kallikrein-related peptidase 13 expression and clinicopathological features in lung squamous cell carcinoma. Mol Clin Oncol. 2023;19(2):64. 10.3892/mco.2023.2660
11 Wang Y, Tan TZ, Wang LQ, Zhang K. LncRNA WT-AS inhibits metastatic ability of non-small cell lung cancer by regulating KLK13. Eur Rev Med Pharmacol Sci. 2020;24(18):9429–37.
12 Gueugnon F, Barascu A, Mavridis K, Petit-Courty A, Marchand-Adam S, Gissot V, et al. Kallikrein-related peptidase 13: An independent indicator of favorable prognosis for patients with nonsmall cell lung cancer. Tumour Biol. 2015;36(7):4979–86. 10.1007/s13277-015-3148-1
13 Kim H, Kang Y, Kim S, Park D, Heo SY, Yoo JS, et al. The host protease KLK5 primes and activates spike proteins to promote human betacoronavirus replication and lung inflammation. Sci Signal. 2024;17(850):eadn3785. 10.1126/scisignal.adn3785
14 Milewska A, Falkowski K, Kulczycka M, Bielecka E, Naskalska A, Mak P, et al. Kallikrein 13 serves as a priming protease during infection by the human coronavirus HKU1. Sci Signal. 2020;13(659):eaba9902. 10.1126/scisignal.aba9902
15 Chen M, Ge Y, Zhang W, Wu P, Cao C. Nasal lavage fluid proteomics reveals potential biomarkers of asthma associated with disease control. J Asthma Allergy. 2024;17:449–62. 10.2147/JAA.S461138
16 National Research Council Committee for the Update of the Guide for the Care and Use of Laboratory Animals. Guide for the Care and Use of Laboratory Animals. Washington, DC: National Academies of Sciences Press (US), 2011. PMid: 21595115.
17 Zeng R, Zhang D, Zhang J, Pan Y, Liu X, Qi Q, et al. Targeting lysyl oxidase like 2 attenuates OVA-induced airway remodeling partly via the AKT signaling pathway. Respir Res. 2024;25(1):230. 10.1186/s12931-024-02811-4
18 Lin Q, Mao W, Wu Q, He X, Li S, Fan Y, et al. Downregulation of KLK13 promotes the invasiveness and metastasis of oesophageal squamous cell carcinoma. Biomed Pharmacother. 2017;96:1008–15. 10.1016/j.biopha.2017.11.129
19 Lu C, Zhang B, Xu T, Zhang W, Bai B, Xiao Z, et al. Piperlongumine reduces ovalbumin-induced asthma and airway inflammation by regulating nuclear factor-κB activation. Int J Mol Med. 2019;44(5):1855–65. 10.3892/ijmm.2019.4322
20 Jia S, Guo P, Lu J, Huang X, Deng L, Jin Y, et al. Curcumol ameliorates lung inflammation and airway remodeling via inhibiting the abnormal activation of the Wnt/β-catenin pathway in chronic asthmatic mice. Drug Des Devel Ther. 2021;15:2641–51. 10.2147/DDDT.S292642
21 Zhang N, Lu HT, Zhang RJ, Sun XJ. Protective effects of methane-rich saline on mice with allergic asthma by inhibiting inflammatory response, oxidative stress and apoptosis. J Zhejiang Univ Sci B. 2019;20(10):828–37. 10.1631/jzus.B1900195
22 Wang Z, Zhang H, Sun X, Ren L. The protective role of vitamin D3 in a murine model of asthma via the suppression of TGF-β/Smad signaling and activation of the Nrf2/HO-1 pathway. Mol Med Rep. 2016;14(3):2389–96. 10.3892/mmr.2016.5563
23 Padra M, Bergwik J, Adler A, Marcoux G, Bhongir RKV, Papareddy P, et al. Tartrate-resistant acid phosphatase 5 (TRAP5) promotes eosinophil migration during allergic asthma. Am J Respir Cell Mol Biol. 2025;73(4):612–22. 10.1165/rcmb.2024-0304OC
24 Lee CC, Chen CH, Kenyon NJ, Wang CN, Tsai HC, Chiu CL, et al. Inhibition of MARCKS phosphorylation attenuates of dendritic cell migration in a murine model of acute asthma. Eur J Pharmacol. 2024;176867. 10.1016/j.ejphar.2024.176867
25 Gon Y, Hashimoto S. Role of airway epithelial barrier dysfunction in pathogenesis of asthma. Allergol Int. 2018;67(1):12–7. 10.1016/j.alit.2017.08.011
26 Chen YF, Huang G, Wang YM, Cheng M, Zhu FF, Zhong JN, et al. Exchange protein directly activated by cAMP (Epac) protects against airway inflammation and airway remodeling in asthmatic mice. Respir Res. 2019;20(1):285. 10.1186/s12931-019-1260-2
27 Lenga Ma Bonda W, Lavergne M, Vasseur V, Brisson L, Roger S, Legras A, et al. Kallikrein-related peptidase 5 contributes to the remodeling and repair of bronchial epithelium. Faseb J. 2021;35(10):e21838. 10.1096/fj.202002649R
28 Willis-Owen SAG, Cookson WOC, Moffatt MF. The genetics and genomics of asthma. Annu Rev Genomics Hum Genet. 2018;19:223–46. 10.1146/annurev-genom-083117-021651
29 Lambrecht BN, Hammad H, Fahy JV. The cytokines of asthma. Immunity. 2019;50(4):975–91. 10.1016/j.immuni.2019.03.018
30 Pritam P, Manna S, Sahu A, Swain SS, Ramchandani S, Bissoyi S, et al. Eosinophil: A central player in modulating pathological complexity in asthma. Allergol Immunopathol (Madr). 2021;49(2):191–207. 10.15586/aei.v49i2.50
31 Kidd P. Th1/Th2 balance: The hypothesis, its limitations, and implications for health and disease. Altern Med Rev. 2003;8(3):223–46.
32 Steinke JW, Borish L. Th2 cytokines and asthma. Interleukin-4: Its role in the pathogenesis of asthma, and targeting it for asthma treatment with interleukin-4 receptor antagonists. Respir Res. 2001;2(2):66–70. 10.1186/rr40
33 Foster PS, Hogan SP, Ramsay AJ, Matthaei KI, Young IG. Interleukin 5 deficiency abolishes eosinophilia, airways hyperreactivity, and lung damage in a mouse asthma model. J Exp Med. 1996;183(1):195–201. 10.1084/jem.183.1.195
34 Wills-Karp M, Luyimbazi J, Xu X, Schofield B, Neben TY, Karp CL, et al. Interleukin-13: Central mediator of allergic asthma. Science. 1998;282(5397):2258–61. 10.1126/science.282.5397.2258
35 Truyen E, Coteur L, Dilissen E, Overbergh L, Dupont LJ, Ceuppens JL, et al. Evaluation of airway inflammation by quantitative Th1/Th2 cytokine mRNA measurement in sputum of asthma patients. Thorax. 2006;61(3):202–8. 10.1136/thx.2005.052399
36 Ezzat DA, Morgan DS, Mohamed RA, Mohamed AF. Genetic association of interleukin 18 (-607C/A, rs1946518) single nucleotide polymorphism with asthmatic children, disease severity and total IgE serum level. Cent Eur J Immunol. 2019;44(3):285–91. 10.5114/ceji.2019.89603
37 Shao Y, Zhou Q, Xue J, Shen B, Ji J, Wei Z. Melatonin ameliorates cisplatin-induced asthenozoospermia via reducing oxidative stress. J Mens Health (JOMH). 2022;18(1):16. 10.31083/jomh.2021.127
38 Ma X, Dong J, Wang Y, Zhang P. Protopine regulates oxidative stress, apoptosis and autophagy in H9C2 cardiomyocytes under hypoxic conditions. Signa Vitae. 2024;20(10):113–20. 10.22514/sv.2024.132
39 Zhang L, Zhang Y. Moscatilin inhibits sevoflurane-induced inflammatory and oxidative stress injury in hippocampal neuronal HT22 cells. Signa Vitae. 2024;20(6):67–73. 10.22514/sv.2024.073
40 Pan D, Ye H, Wang J, Mao J. Gentianine facilitates proliferation and inhibits inflammation and oxidative stress in caerulein-triggered acute pancreatitis cell model. Signa Vitae. 2024;20(5):77–84.
41 Zhang C, Xie M, Wang Y, Han T. Tussilagone inhibits inflammation and oxidative stress to alleviate acute pancreatitis. Signa Vitae. 2024;20(1):133–39.
42 Al-Afaleg NO, Al-Senaidy A, El-Ansary A. Oxidative stress and antioxidant status in Saudi asthmatic patients. Clin Biochem. 2011;44(8–9):612–7. 10.1016/j.clinbiochem.2011.01.016
43 Michaeloudes C, Abubakar-Waziri H, Lakhdar R, Raby K, Dixey P, Adcock IM, et al. Molecular mechanisms of oxidative stress in asthma. Mol Aspects Med. 2022;85:101026. 10.1016/j.mam.2021.101026
44 Gwarzo MY, Muhammad SA. Extracellular superoxide dismutase activity and plasma malondialdehyde in human immunodeficiency virus subjects of Kano state as surrogate markers of CD4 status. Int J Biomed Sci. 2010;6(4):294–300. 10.59566/IJBS.2010.6294
45 Jin Y, Huang J, Ma N. In vitro effects of ganoderic acid A on NF-κB-mediated inflammatory response in caerulein-stimulated pancreatic acinar cells. Signa Vitae. 2024;20(6):93–8. 10.22514/sv.2024.075
46 Pan D, Rao X, Gong M, Zhou J. Polygonatum cyrtonema Hua polysaccharides regulates NF-κB and Nrf2 pathways to alleviates oxidative stress and neuroinflammation in cerebral ischemia/reperfusion injury. Signa Vitae. 2024;20(12):108–15. 10.22514/sv.2024.162
47 Mathes E, O’Dea EL, Hoffmann A, Ghosh G. NF-kappa B dictates the degradation pathway of Ikappa B alpha. Embo J. 2008;27(9):1357–67. 10.1038/emboj.2008.73
48 Liu T, Zhang L, Joo D, Sun SC. NF-κB signaling in inflammation. Signal Transduct Target Ther. 2017;2:17023. 10.1038/sigtrans.2017.23
49 Trejo Bittar HE, Yousem SA, Wenzel SE. Pathobiology of severe asthma. Annu Rev Pathol. 2015;10:511–45. 10.1146/annurev-pathol-012414-040343
50 Dong J, Liao W, Peh HY, Chan TK, Tan WS, Li L, et al. Ribosomal protein S3 gene silencing protects against experimental allergic asthma. Br J Pharmacol. 2017;174(7):540–52. 10.1111/bph.13717
51 Gu X, Zhang Q, Du Q, Shen H, Zhu Z. Pinocembrin attenuates allergic airway inflammation via inhibition of NF-κB pathway in mice. Int Immunopharmacol. 2017;53:90–5. 10.1016/j.intimp.2017.10.005