Inhibitory Effect of S100A11 on Airway Smooth Muscle Contraction and Airway Hyperresponsiveness

Abstract

Objective

S100A11 is a member of the S100 calcium-binding protein family and has intracellular and extracellular regulatory activities. We previously reported that S100A11 was differentially expressed in the respiratory tracts of asthmatic rats as compared with normal controls. Here, we aimed to analyze the potential of S100A11 to regulate both allergen-induced airway hyperresponsiveness (AHR) as well as acetylcholine (ACh)-induced hypercontractility of airway smooth muscle (ASM) and contraction of ASM cells (ASMCs).

Methods

Purified recombinant rat S100A11 protein (rS100A11) was administered to OVA-sensitized and challenged rats and then the AHR of animals was measured. The relaxation effects of rS100A11 on ASM were detected using isolated tracheal rings and primary ASMCs. The expression levels of un-phosphorylated myosin light chain (MLC) and phosphorylated MLC in ASMCs were analyzed using Western blotting.

Results

Treatment with rS100A11 attenuated AHR in the rats. ASM contraction assays showed that rS100A11 reduced the contractile responses of isolated tracheal rings and primary ASMCs treated with ACh. In addition, rS100A11 markedly decreased the ACh-induced phosphorylation of the myosin light chain in ASMCs. Moreover, rS100A11 also suppressed the contractile response of tracheal rings in calcium-free buffer medium.

Conclusion

These results indicate that S100A11 protein can relieve AHR by relaxing ASM independently of extracellular calcium. Our data support the idea that S100A11 is a potential therapeutic target for reducing airway resistance in asthma patients.

Keywords

S100A11 / asthma / airway hyperresponsiveness / airway smooth muscle / relaxation

References

[1] OliverBG, BlackJL. Airway Smooth Muscle and Asthma. Allergol Int, 2006, 55(3): 215-223

[2] McGrawDW, LiggettSB. Molecular mechanisms of beta2-adrenergic receptor function and regulation. Proc Am Thorac Soc, 2005, 2(4): 292-296 discussion 311–292

[3] YimRP, KoumbourlisAC. Tolerance & resistance to beta(2)-agonist bronchodilators. Paediatr Respir Rev, 2013, 14(3): 195-198

[4] AdhikariBB, WangK. S100A1 modulates skeletal muscle contraction by desensitizing calcium activation of isometric tension, stiffness and ATPase. FEBS Lett, 2001, 497(2–3): 95-98

[5] WangW, AspML, Guerrero-SernaG, et al.. Differential effects of S100 proteins A2 and A6 on cardiac Ca(2+) cycling and contractile performance. J Mol Cell Cardiol, 2014, 72: 117-125

[6] ZhangW, GunstSJ. S100A4 is activated by RhoA and catalyses the polymerization of non-muscle myosin, adhesion complex assembly and contraction in airway smooth muscle. J Physiol, 2020, 598(20): 4573-4590

[7] GorslerT, MurzikU, UlbrichtT, et al.. DNA damage-induced translocation of S100A11 into the nucleus regulates cell proliferation. BMC Cell Biol, 2010, 11: 100

[8] WangC, ZhangZ, LiL, et al.. S100A11 is a migration-related protein in laryngeal squamous cell carcinoma. Int J Med Sci, 2013, 10(11): 1552-1559

[9] XiaQ, LiX, ZhouH, et al.. S100A11 protects against neuronal cell apoptosis induced by cerebral ischemia via inhibiting the nuclear translocation of annexin A1. Cell Death Dis, 2018, 9(6): 657

[10] JaiswalJK, LauritzenSP, SchefferL, et al.. S100A11 is required for efficient plasma membrane repair and survival of invasive cancer cells. Nat Commun, 2014, 5(1): 3795

[11] Andres CerezoL, SumovaB, PrajzlerovaK, et al.. Calgizzarin (S100A11): a novel inflammatory mediator associated with disease activity of rheumatoid arthritis. Arthritis Res Ther, 2017, 19(1): 79

[12] ZhaoXQ, NakaM, MuneyukiM, et al.. Ca2+-Dependent Inhibition of Actin-Activated Myosin ATPase Activity by S100C (S100A11), a Novel Member of the S100 Protein Family. Biochem Biophys Res Commun, 2000, 267(1): 77-79

[13] FanC, FuZ, SuQ, et al.. S100A11 mediates hypoxia-induced mitogenic factor (HIMF)-induced smooth muscle cell migration, vesicular exocytosis, and nuclear activation. Mol Cell Proteomics, 2011, 10(3): M110000901

[14] Santamaria-KisielL, Rintala-DempseyAC, ShawGS. Calcium-dependent and -independent interactions of the S100 protein family. Biochem J, 2006, 396(2): 201-214

[15] XuYD, CuiJM, WangY, et al.. The early asthmatic response is associated with glycolysis, calcium binding and mitochondria activity as revealed by proteomic analysis in rats. Respir Res, 2010, 11: 107

[16] XuY, YinL, ParkGH, et al.. Serum from asthmatic rat treated with acupuncture inhibits acetylcholine- induced contractile responses of airway smooth muscle cells. J Tradit Chin Med, 2017, 37(1): 101-107

[17] XuYD, WangY, YinLM, et al.. S100A8 protein attenuates airway hyperresponsiveness by suppressing the contraction of airway smooth muscle. Biochem Biophys Res Commun, 2017, 484(1): 184-188

[18] BresnickAR. S100 proteins as therapeutic targets. Biophys Rev, 2018, 10(6): 1617-1629

[19] AokiT, MatsumotoY, HirataK, et al.. Expression profiling of genes related to asthma exacerbations. Clin Exp Allergy, 2009, 39(2): 213-221

[20] KangJH, HwangSM, ChungIY. S100A8, S100A9 and S100A12 activate airway epithelial cells to produce MUC5AC via extracellular signal-regulated kinase and nuclear factor-kappaB pathways. Immunology, 2015, 144(1): 79-90

[21] XuYD, WeiY, WangY, et al.. Exogenous S100A8 protein inhibits PDGF-induced migration of airway smooth muscle cells in a RAGE-dependent manner. Biochem Biophys Res Commun, 2016, 472(1): 243-249

[22] YinLM, LiHY, ZhangQH, et al.. Effects of S100A9 in a rat model of asthma and in isolated tracheal spirals. Biochem Biophys Res Commun, 2010, 398(3): 547-552

[23] DaveyGE, MurmannP, HoechliM, et al.. Calcium-dependent translocation of S100A11 requires tubulin filaments. Biochim Biophys Acta, 2000, 1498(2–3): 220-232

[24] RétyS, OsterlohD, AriéJP, et al.. Structural basis of the Ca2+-dependent association between S100C (S100A11) and its target, the N-terminal part of annexin I. Structure, 2000, 8(2): 175-184

[25] ChangN, SutherlandC, HesseE, et al.. Identification of a novel interaction between the Ca2+-binding protein S100A11 and the Ca2+- and phospholipid-binding protein annexin A6. Am J Physiol Cell Physiol, 2007, 292(4): C1417-C1430

[26] HuangYK, ChouRH, YuC. Tranilast Blocks the Interaction between the Protein S100A11 and Receptor for Advanced Glycation End Products (RAGE) V Domain and Inhibits Cell Proliferation. J Biol Chem, 2016, 291(27): 14300-14310

[27] SakaguchiM, SonegawaH, MurataH, et al.. S100A11, an Dual Mediator for Growth Regulation of Human Keratinocytes. Mol Biol Cell, 2008, 19(1): 78-85

[28] TakamatsuH, YamamotoKI, TomonobuN, et al.. Extracellular S100A11 Plays a Critical Role in Spread of the Fibroblast Population in Pancreatic Cancers. Oncol Res, 2019, 27(6): 713-727

[29] Andres CerezoL, HulejovaH, SumovaB, et al.. Pro-inflammatory S100A11 is elevated in inflammatory myopathies and reflects disease activity and extra-muscular manifestations in myositis. Cytokine, 2019, 116: 13-20

[30] CecilDL, TerkeltaubR. Transamidation by transglu-taminase 2 transforms S100A11 calgranulin into a procatabolic cytokine for chondrocytes. J Immunol, 2008, 180(12): 8378-8385