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Cysteinyl leukotriene D4 (LTD4) promotes airway epithelial cell inflammation and remodelling

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Abstract

Objective

Cysteinyl leukotrienes (CysLTs), a group of inflammatory lipid mediators, are found elevated in obese-asthmatic patients. Leukotriene D4 (LTD4), a representative CysLT, is implicated in promoting lung inflammation and remodelling in allergic asthma, but its role in non-allergic asthma, especially in obese-asthmatic patients, is not known. Here, using primary human small airway epithelial cells (SAECs) we have investigated the mechanism of LTD4-induced inflammation and remodelling and assessed high proneness of obese mice to develop asthma upon challenge with allergen ovalbumin (OVA).

Methods

Primary human small airway epithelial cells (SAECs) were stimulated with different concentrations of LTD4 for different time intervals and various inflammatory markers were measured through cytokine array, membrane-based ELISA and Western blotting. An air–liquid interface (ALI) model of SAECs was used to study the effects of LTD4-induced remodelling in SAECs using Western blotting, H&E staining and PAS staining. Further, OVA-based murine model was used to examine the propensity of high-fat diet (HFD)-fed obese mice to develop asthma symptoms by studying the infiltration of inflammatory cells (assessed by bronchioalveolar lavage (BAL) cytology) and airway remodelling (assessed by histopathology) upon allergen exposure.

Results

The human primary small airway epithelial cells (SAECs) treated with LTD4 showed significant alterations in the levels of inflammatory markers such as GM-CSF, TNF-α, IL-1β, EGF and eotaxin in dose- and time-dependent manner. Further, LTD4 enhanced the activation of inflammasomes as evidenced by increased levels of NALP3, cleaved caspase-1 and IL-1β. LTD4 also enhanced inflammation by increasing the expression of COX-2 in SAECs. The airway remodelling markers Vimentin and Muc5AC were found elevated in ALI culture of SAECs when stimulated with LTD4, as it also increased TGF-β levels and activation of Smad2/3 phosphorylation in SAECs. Last, sensitization and challenge of HFD-fed obese mice with OVA showed increased infiltration of inflammatory cells in BAL and enhanced levels of remodeling phenotypes like loss of cilia, mucus cell metaplasia and collagen deposition in mice lung tissues.

Conclusion

The results suggest that LTD4 could induce inflammatory response in human airway epithelial cell by activating NALP3 inflammasome. LTD4 could further promote airway epithelial cells’ remodelling through TGF-β/smad2/3-mediated pathway. Our in vivo results suggested that obesity predisposed the OVA challenged mice to develop lung inflammation and remodelling akin to asthma-like phenotypes during obesity.

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Acknowledgements

Neeraj Dholia acknowledges the receipt of Rajiv Gandhi National Fellowship from University Grant Commission (UGC), Government of India. Gurupreet S. Sethi acknowledges the UGC-BSR Senior Research Fellowship from UGC. Umesh C. S. Yadav thankfully acknowledges the award of Ramanujan Fellowship (SR/S2/RJN-102/2012) by Department of Science & Technology (DST)/Science and Engineering Research Board (SERB), Government of India. The Ramalingaswami Fellowship from Department of Biotechnology, Government of India (BT/RLF/Re-entry/36/2012) to Amarjit S. Naura is also acknowledged.

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Authors and Affiliations

  1. School of Life Sciences, Central University of Gujarat, Sector 30, Gandhinagar, Gujarat, 382030, India

    Neeraj Dholia

  2. Center for Autoimmunity and Inflammation, La Jolla Institute for Immunology, 9420 Athena Circle, La Jolla, CA, 92037, USA

    Gurupreet S. Sethi

  3. Department of Biochemistry, Panjab University, Chandigarh, 160014, India

    Amarjit S. Naura

  4. Special Centre for Molecular Medicine (SCMM), Jawaharlal Nehru University (JNU), 3C (First Floor), SCMM, JNU, New Delhi, 110067, India

    Umesh C. S. Yadav

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  1. Neeraj Dholia
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  2. Gurupreet S. Sethi
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  4. Umesh C. S. Yadav
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Correspondence to Umesh C. S. Yadav.

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Dholia, N., Sethi, G.S., Naura, A.S. et al. Cysteinyl leukotriene D4 (LTD4) promotes airway epithelial cell inflammation and remodelling. Inflamm. Res. 70, 109–126 (2021). https://doi.org/10.1007/s00011-020-01416-z

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  • DOI: https://doi.org/10.1007/s00011-020-01416-z

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