Kiss1 receptor knockout exacerbates airway hyperresponsiveness and remodeling in a mouse model of allergic asthma.
Airway inflammation
Airway smooth muscle
Asthma
FlexiVent
Lung function
α-smooth muscle actin
Journal
Respiratory research
ISSN: 1465-993X
Titre abrégé: Respir Res
Pays: England
ID NLM: 101090633
Informations de publication
Date de publication:
28 Oct 2024
28 Oct 2024
Historique:
received:
06
09
2024
accepted:
20
10
2024
medline:
29
10
2024
pubmed:
29
10
2024
entrez:
29
10
2024
Statut:
epublish
Résumé
In asthma, sex-steroids signaling is recognized as a critical regulator of disease pathophysiology. However, the paradoxical role of sex-steroids, especially estrogen, suggests that an upstream mechanism or even independent of estrogen plays an important role in regulating asthma pathophysiology. In this context, in our previous studies, we explored kisspeptin (Kp) and its receptor Kiss1R's signaling in regulating human airway smooth muscle cell remodeling in vitro and airway hyperresponsiveness (AHR) in vivo in a mouse (wild-type, WT) model of asthma. In this study, we evaluated the effect of endogenous Kp in regulating AHR and remodeling using Kiss1R knockout (Kiss1R C57BL/6J WT (Kiss1R Interestingly, the loss of Kiss1R exacerbated lung function and airway contractility in mice challenged with MA, with more profound effects in Kiss1R These findings demonstrate the importance of inherent Kiss1R signaling in regulating airway inflammation, AHR, and remodeling in the pathophysiology of asthma.
Sections du résumé
BACKGROUND
BACKGROUND
In asthma, sex-steroids signaling is recognized as a critical regulator of disease pathophysiology. However, the paradoxical role of sex-steroids, especially estrogen, suggests that an upstream mechanism or even independent of estrogen plays an important role in regulating asthma pathophysiology. In this context, in our previous studies, we explored kisspeptin (Kp) and its receptor Kiss1R's signaling in regulating human airway smooth muscle cell remodeling in vitro and airway hyperresponsiveness (AHR) in vivo in a mouse (wild-type, WT) model of asthma. In this study, we evaluated the effect of endogenous Kp in regulating AHR and remodeling using Kiss1R knockout (Kiss1R
METHODS
METHODS
C57BL/6J WT (Kiss1R
RESULTS
RESULTS
Interestingly, the loss of Kiss1R exacerbated lung function and airway contractility in mice challenged with MA, with more profound effects in Kiss1R
CONCLUSIONS
CONCLUSIONS
These findings demonstrate the importance of inherent Kiss1R signaling in regulating airway inflammation, AHR, and remodeling in the pathophysiology of asthma.
Identifiants
pubmed: 39468619
doi: 10.1186/s12931-024-03017-4
pii: 10.1186/s12931-024-03017-4
doi:
Substances chimiques
Receptors, Kisspeptin-1
0
Kiss1r protein, mouse
0
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
387Subventions
Organisme : NHLBI NIH HHS
ID : R01-HL146705
Pays : United States
Organisme : NIGMS COBRE award
ID : 1P20-GM109024
Informations de copyright
© 2024. The Author(s).
Références
Chiarella SE, Cardet JC, Prakash Y, editors. Sex, cells, and asthma. Mayo Clin Proc. 2021;96(7):1955–1969.
Ambhore NS, Kalidhindi RSR, Sathish V. Sex-Steroid Signaling in Lung diseases and inflammation. Adv Exp Med Biol. 2021;1303:243–73.
pubmed: 33788197
pmcid: 8212875
doi: 10.1007/978-3-030-63046-1_14
Wu M, Wu Q, Liu D, Zu W, Zhang D, Chen L. The global burden of lower respiratory infections attributable to respiratory syncytial virus in 204 countries and territories, 1990–2019: findings from the global burden of Disease Study 2019. Intern Emerg Med. 2024;19(1):59–70.
pubmed: 37789183
doi: 10.1007/s11739-023-03438-x
Hernandez-Lara MA, Richard J, Deshpande DA. Diacylglycerol Kinase is a Keystone Regulator of Signaling relevant to the pathophysiology of Asthma. Am J Physiol Lung Cell Mol Physiol. 2024;327(1):L3–18.
pubmed: 38742284
doi: 10.1152/ajplung.00091.2024
Ambhore NS, Balraj P, Pabelick CM, Prakash Y, Sathish V. Estrogen receptors differentially modifies lamellipodial and focal adhesion dynamics in airway smooth muscle cell migration. Mol Cell Endocrinol. 2024;579:112087.
pubmed: 37827228
doi: 10.1016/j.mce.2023.112087
Akkenepally SV, Yombo DJ, Yerubandi S, Reddy GB, Deshpande DA, McCormack FX, et al. Interleukin 31 receptor α promotes smooth muscle cell contraction and airway hyperresponsiveness in asthma. Nat Commun. 2023;14(1):8207.
pubmed: 38081868
pmcid: 10713652
doi: 10.1038/s41467-023-44040-1
Burgess JK. Connective tissue growth factor: a role in airway remodelling in asthma? Clin Exp Pharmacol Physiol. 2005;32(11):988–94.
pubmed: 16405457
doi: 10.1111/j.1440-1681.2005.04296.x
Prakash Y. Airway smooth muscle in airway reactivity and remodeling: what have we learned? Am J Physiol Lung Cell Mol Physiol. 2013;305(12):L912–33.
pubmed: 24142517
pmcid: 3882535
doi: 10.1152/ajplung.00259.2013
Sathish V, Martin YN, Prakash Y. Sex steroid signaling: implications for lung diseases. Pharmacol Ther. 2015;150:94–108.
pubmed: 25595323
pmcid: 4523383
doi: 10.1016/j.pharmthera.2015.01.007
Borkar NA, Ambhore NS, Balraj P, Ramakrishnan YS, Sathish V. Kisspeptin regulates airway hyperresponsiveness and remodeling in a mouse model of asthma. J Pathol. 2023;260(3):339–52.
pubmed: 37171283
pmcid: 10759912
doi: 10.1002/path.6086
Holgate ST, Arshad HS, Roberts GC, Howarth PH, Thurner P, Davies DE. A new look at the pathogenesis of asthma. Clin Sci (Lond). 2010;118(7):439–50.
doi: 10.1042/CS20090474
Hough KP, Curtiss ML, Blain TJ, Liu RM, Trevor J, Deshane JS, et al. Airway Remodeling in Asthma. Front Med (Lausanne). 2020;7:191.
pubmed: 32509793
doi: 10.3389/fmed.2020.00191
Royce SG, Tang ML. The effects of current therapies on airway remodeling in asthma and new possibilities for treatment and prevention. Curr Mol Pharmacol. 2009;2(2):169–81.
pubmed: 20021456
doi: 10.2174/1874467210902020169
Wasti B, Chen Z, He Y, Duan WT, Liu S-K, Xiang X-D. Role of sex hormones at different physiobiological conditions and therapeutic potential in MBD2 mediated severe asthma. Oxid Med Cell Longev. 2021;2021:7097797.
pubmed: 35096261
pmcid: 8799366
doi: 10.1155/2021/7097797
Prakash Y. Emerging concepts in smooth muscle contributions to airway structure and function: implications for health and disease. Am J Physiol Lung Cell Mol Physiol. 2016;311(6):L1113–40.
pubmed: 27742732
pmcid: 5206394
doi: 10.1152/ajplung.00370.2016
Keselman A, Heller N. Estrogen signaling modulates allergic inflammation and contributes to sex differences in asthma. Front Immunol. 2015;6:152158.
doi: 10.3389/fimmu.2015.00568
Monteiro R, Teixeira D, Calhau C. Estrogen signaling in metabolic inflammation. Mediators Inflamm. 2014;2014:615917.
pubmed: 25400333
pmcid: 4226184
doi: 10.1155/2014/615917
Cephus JY, Gandhi VD, Shah R, Brooke Davis J, Fuseini H, Yung JA, et al. Estrogen receptor-α signaling increases allergen‐induced IL‐33 release and airway inflammation. Allergy. 2021;76(1):255–68.
pubmed: 32648964
doi: 10.1111/all.14491
Townsend EA, Miller VM, Prakash YS. Sex differences and sex steroids in lung health and disease. Endocr Rev. 2012;33(1):1–47.
pubmed: 22240244
pmcid: 3365843
doi: 10.1210/er.2010-0031
Ambhore NS, Kalidhindi RSR, Loganathan J, Sathish V. Role of differential estrogen receptor activation in airway hyperreactivity and remodeling in a murine model of asthma. Am J Respir Cell Mol Biol. 2019;61(4):469–80.
pubmed: 30958966
pmcid: 6775953
doi: 10.1165/rcmb.2018-0321OC
Lee EB, Dilower I, Marsh CA, Wolfe MW, Masumi S, Upadhyaya S, et al. Sex Dimorphism Kisspeptin Signal Cells. 2022;11(7):1146.
pubmed: 35406710
Frazao R, Cravo RM, Donato J, Ratra DV, Clegg DJ, Elmquist JK, et al. Shift in Kiss1 cell activity requires estrogen receptor α. J Neurosci. 2013;33(7):2807–20.
pubmed: 23407940
pmcid: 3713640
doi: 10.1523/JNEUROSCI.1610-12.2013
Smith JT, Cunningham MJ, Rissman EF, Clifton DK, Steiner RA. Regulation of Kiss1 gene expression in the brain of the female mouse. Endocrinology. 2005;146(9):3686–92.
pubmed: 15919741
doi: 10.1210/en.2005-0488
Lee JH, Welch DR. Suppression of metastasis in human breast carcinoma MDA-MB-435 cells after transfection with the metastasis suppressor gene, KiSS-1. Cancer Res. 1997;57(12):2384–7.
pubmed: 9192814
Ohtaki T, Shintani Y, Honda S, Matsumoto H, Hori A, Kanehashi K, et al. Metastasis suppressor gene KiSS-1 encodes peptide ligand of a G-protein-coupled receptor. Nature. 2001;411(6837):613–7.
pubmed: 11385580
doi: 10.1038/35079135
Borkar NA, Ambhore NS, Kalidhindi RSR, Pabelick CM, Prakash YS, Sathish V. Kisspeptins inhibit human airway smooth muscle proliferation. JCI Insight. 2022;7(10):e152762.
pubmed: 35420998
pmcid: 9220928
doi: 10.1172/jci.insight.152762
Harter CJL, Kavanagh GS, Smith JT. The role of kisspeptin neurons in reproduction and metabolism. J Endocrinol. 2018;238(3):R173–83.
pubmed: 30042117
doi: 10.1530/JOE-18-0108
Balraj P, Ambhore NS, Ramakrishnan YS, Borkar NA, Banerjee P, Reza MI, et al. Kisspeptin/KISS1R signaling modulates human airway smooth muscle cell Migration. Am J Respir Cell Mol Biol. 2024;70(6):507–18.
pubmed: 38512807
doi: 10.1165/rcmb.2023-0469OC
Wang CJ, Smith JT, Lu D, Noble PB, Wang KCW. Airway-associated adipose tissue accumulation is increased in a kisspeptin receptor knockout mouse model. Clin Sci (Lond). 2023;137(19):1547–62.
pubmed: 37732890
doi: 10.1042/CS20230792
Tolson KP, Marooki N, Wolfe A, Smith JT, Kauffman AS. Cre/lox generation of a novel whole-body Kiss1r KO mouse line recapitulates a hypogonadal, obese, and metabolically-impaired phenotype. Mol Cell Endocrinol. 2019;498:110559.
pubmed: 31442544
pmcid: 6814569
doi: 10.1016/j.mce.2019.110559
National Research Council (US). Committee for the update of the guide for the Care and Use of Laboratory animals. Guide for the Care and Use of Laboratory animals. 8th ed. Washington (DC): National Academies Press (US); 2011.
Kalidhindi RS, Ambhore NS, Bhallamudi S, Loganathan J, Sathish V. Role of Estrogen Receptors α and β in a murine model of Asthma: exacerbated Airway Hyperresponsiveness and remodeling in ERβ knockout mice. Front Pharmacol. 2019;10:1499.
pubmed: 32116656
doi: 10.3389/fphar.2019.01499
Fallon PG, Schwartz C. The high and lows of type 2 asthma and mouse models. J Allergy Clin Immunol. 2020;145(2):496–8.
pubmed: 31812572
doi: 10.1016/j.jaci.2019.11.031
Kalidhindi RSR, Ambhore NS, Balraj P, Schmidt T, Khan MN, Sathish V. Androgen receptor activation alleviates airway hyperresponsiveness, inflammation, and remodeling in a murine model of asthma. Am J Physiol Lung Cell Mol Physiol. 2021;320(5):L803–18.
pubmed: 33719566
pmcid: 8174830
doi: 10.1152/ajplung.00441.2020
Yarova PL, Stewart AL, Sathish V, Britt RD Jr, Thompson MA, Lowe P. Calcium-sensing receptor antagonists abrogate airway hyperresponsiveness and inflammation in allergic asthma. Sci Transl Med. 2015;7(284):ra28460–60.
doi: 10.1126/scitranslmed.aaa0282
Kalidhindi RSR, Ambhore NS, Sathish V. Cellular and biochemical analysis of bronchoalveolar lavage fluid from murine lungs. Anim Models Allergic Disease: Methods Mol Biol. 2021;2223:201–15.
doi: 10.1007/978-1-0716-1001-5_15
Loganathan J, Pandey R, Ambhore NS, Borowicz P, Sathish V. Laser-capture microdissection of murine lung for differential cellular RNA analysis. Cell Tissue Res. 2019;376(3):425–32.
pubmed: 30710174
pmcid: 6534428
doi: 10.1007/s00441-019-02995-y
Raju KRS, Kumar MS, Gupta S, Naga ST, Shankar JK, Murthy V, et al. 5-Aminosalicylic acid attenuates allergen-induced airway inflammation and oxidative stress in asthma. Pulm Pharmacol Ther. 2014;29(2):209–16.
pubmed: 25101553
doi: 10.1016/j.pupt.2014.07.007
Cho JY, Miller M, Baek KJ, Castaneda D, Nayar J, Roman M, et al. Immunostimulatory DNA sequences inhibit respiratory syncytial viral load, airway inflammation, and mucus secretion. J Allergy Clin Immunol. 2001;108(5):697–702.
pubmed: 11692091
doi: 10.1067/mai.2001.119918
Yang Q, Miao Q, Chen H, Li D, Luo Y, Chiu J, et al. Myocd regulates airway smooth muscle cell remodeling in response to chronic asthmatic injury. J Pathol. 2023;259(3):331–41.
pubmed: 36484734
pmcid: 10107741
doi: 10.1002/path.6044
Kalidhindi RSR, Borkar NA, Ambhore NS, Pabelick CM, Prakash Y, Sathish V. Sex steroids skew ACE2 expression in human airway: a contributing factor to sex differences in COVID-19? Am J Physiol Lung Cell Mol Physiol. 2020;319(5):L843–7.
pubmed: 32996784
pmcid: 7789973
doi: 10.1152/ajplung.00391.2020
Nayak AP, Deshpande DA, Shah SD, Villalba DR, Yi R, Wang N, et al. OGR1-dependent regulation of the allergen-induced asthma phenotype. Am J Physiol Lung Cell Mol Physiol. 2021;321(6):L1044–54.
pubmed: 34668419
pmcid: 8715030
doi: 10.1152/ajplung.00200.2021
Wang X, Yang X, Li Y, Wang X, Zhang Y, Dai X, et al. Lyn kinase represses mucus hypersecretion by regulating IL-13-induced endoplasmic reticulum stress in asthma. EBioMedicine. 2017;15:137–49.
pubmed: 28024734
doi: 10.1016/j.ebiom.2016.12.010
Nayak AP, Deshpande DA, Penn RB. New targets for resolution of airway remodeling in obstructive lung diseases. F1000Res. 2018;7:F1000.
pubmed: 29904584
pmcid: 5981194
doi: 10.12688/f1000research.14581.1
Ambhore NS, Katragadda R, Kalidhindi RSR, Thompson MA, Pabelick CM, Prakash Y, et al. Estrogen receptor beta signaling inhibits PDGF induced human airway smooth muscle proliferation. Mol Cell Endocrinol. 2018;476:37–47.
pubmed: 29680290
pmcid: 6120801
doi: 10.1016/j.mce.2018.04.007
Ambhore NS, Kumar A, Sathish V. Molecular determinants of airway smooth muscle cells in health and disease. Ann Transl Med. 2022;10(20):1084.
pubmed: 36388811
pmcid: 9652533
doi: 10.21037/atm-22-4478
Bhattacharyya S, Wang W, Morales-Nebreda L, Feng G, Wu M, Zhou X, et al. Tenascin-C drives persistence of organ fibrosis. Nat Commun. 2016;7(1):11703.
pubmed: 27256716
pmcid: 4895803
doi: 10.1038/ncomms11703
Boulet L-P. Airway remodeling in asthma: update on mechanisms and therapeutic approaches. Curr Opin Pulm Med. 2018;24(1):56–62.
pubmed: 29076828
doi: 10.1097/MCP.0000000000000441
Fang L, Sun Q, Roth M. Immunologic and non-immunologic mechanisms leading to airway remodeling in asthma. Int J Mol Sci. 2020;21(3):757.
pubmed: 31979396
pmcid: 7037330
doi: 10.3390/ijms21030757
Bergeron C, Tulic MK, Hamid Q. Airway remodelling in asthma: from benchside to clinical practice. Can Respir J. 2010;17(4):e85–93.
pubmed: 20808979
pmcid: 2933777
doi: 10.1155/2010/318029
Murdoch JR, Lloyd CM. Chronic inflammation and asthma. Mutat Res. 2010;690(1–2):24–39.
pubmed: 19769993
pmcid: 2923754
doi: 10.1016/j.mrfmmm.2009.09.005
O’Byrne PM, Inman MD. Airway hyperresponsiveness. Chest. 2003;123(3 Suppl):s411–6.
doi: 10.1378/chest.123.3_suppl.411S
Busse WW. The relationship of airway hyperresponsiveness and airway inflammation: Airway hyperresponsiveness in asthma: its measurement and clinical significance. Chest. 2010;138(2 Suppl):s4–10.
doi: 10.1378/chest.10-0100
Huang Y, Qiu C. Research advances in airway remodeling in asthma: a narrative review. Ann Transl Med. 2022;10(18):1023.
pubmed: 36267708
pmcid: 9577744
doi: 10.21037/atm-22-2835
Uenoyama Y, Inoue N, Nakamura S, Tsukamura H. Kisspeptin neurons and estrogen–estrogen receptor α signaling: unraveling the mystery of steroid feedback system regulating mammalian reproduction. Int J Mol Sci. 2021;22(17):9229.
pubmed: 34502135
pmcid: 8430864
doi: 10.3390/ijms22179229
West AR, Syyong HT, Siddiqui S, Pascoe CD, Murphy TM, Maarsingh H, et al. Airway contractility and remodeling: links to asthma symptoms. Pulm Pharmacol Ther. 2013;26(1):3–12.
pubmed: 22989721
doi: 10.1016/j.pupt.2012.08.009
Johnson M. Molecular mechanisms of β2-adrenergic receptor function, response, and regulation. J Allergy Clin Immunol. 2006;117(1):18–24.
pubmed: 16387578
doi: 10.1016/j.jaci.2005.11.012
Lei Z, Bai X, Ma J, Yu Q. Kisspeptin–13 inhibits bleomycin–induced pulmonary fibrosis through GPR54 in mice. Mol Med Rep. 2019;20(2):1049–56.
pubmed: 31173221
pmcid: 6625411
Toews G. Cytokines and the lung. Eur Respir J. 2001;18(34 suppl):s3–17.
doi: 10.1183/09031936.01.00266001
Chung KF, Patel HJ, Fadlon EJ, Rousell J, Haddad EB, Jose PJ, et al. Induction of eotaxin expression and release from human airway smooth muscle cells by IL-1β and TNFα: effects of IL‐10 and corticosteroids. Br J Pharmacol. 1999;127(5):1145–50.
pubmed: 10455260
pmcid: 1566131
doi: 10.1038/sj.bjp.0702660
Wang G, Petzke MM, Iyer R, Wu H, Schwartz I. Pattern of proinflammatory cytokine induction in RAW264. 7 mouse macrophages is identical for virulent and attenuated Borrelia burgdorferi. J Immunol. 2008;180(12):8306–15.
pubmed: 18523297
doi: 10.4049/jimmunol.180.12.8306
Wang D, Wu Z, Zhao C, Yang X, Wei H, Liu M, et al. KP-10/Gpr54 attenuates rheumatic arthritis through inactivating NF-κB and MAPK signaling in macrophages. Pharmacol Res. 2021;171:105496.
pubmed: 33609696
doi: 10.1016/j.phrs.2021.105496
Conroy DM, Williams TJ. Eotaxin and the attraction of eosinophils to the asthmatic lung. Respir Res. 2001;2(3):150–7.
pubmed: 11686879
pmcid: 2002069
doi: 10.1186/rr52
Davoine F, Lacy P. Eosinophil cytokines, chemokines, and growth factors: emerging roles in immunity. Front Immunol. 2014;5:117061.
doi: 10.3389/fimmu.2014.00570
Yokoyama A, Kohno N, Fujino S, Hamada H, Inoue Y, Fujioka S, et al. Circulating interleukin-6 levels in patients with bronchial asthma. Am J Respir Crit Care Med. 1995;151(5):1354–8.
pubmed: 7735584
doi: 10.1164/ajrccm.151.5.7735584
Deetz DC, Jagielo PJ, Quinn TJ, Thorne PS, Bleuer SA, Schwartz DA. The kinetics of grain dust-induced inflammation of the lower respiratory tract. Am J Respir Crit Care Med. 1997;155(1):254–9.
pubmed: 9001321
doi: 10.1164/ajrccm.155.1.9001321
Kwak D-W, Park D, Kim J-H. Leukotriene B4 receptor 2 mediates the production of G-CSF that plays a critical role in steroid-resistant neutrophilic airway inflammation. Biomedicines. 2022;10(11):2979.
pubmed: 36428547
pmcid: 9687517
doi: 10.3390/biomedicines10112979
Kim Y-M, Kim H, Lee S, Kim S, Lee J-U, Choi Y, et al. Airway G-CSF identifies neutrophilic inflammation and contributes to asthma progression. Eur Respir J. 2020;55(2):1900827.
pubmed: 31744834
doi: 10.1183/13993003.00827-2019
Choi IS, Cui Y, Koh Y-A, Lee H-C, Cho Y-B, Won Y-H. Effects of dehydroepiandrosterone on Th2 cytokine production in peripheral blood mononuclear cells from asthmatics. Korean J Intern Med. 2008;23(4):176–81.
pubmed: 19119254
pmcid: 2687683
doi: 10.3904/kjim.2008.23.4.176
Raundhal M, Morse C, Khare A, Oriss TB, Milosevic J, Trudeau J, et al. High IFN-γ and low SLPI mark severe asthma in mice and humans. J Clin Invest. 2015;125(8):3037–50.
pubmed: 26121748
pmcid: 4563754
doi: 10.1172/JCI80911