Structure-Function Analysis of CCL28 in the Development of Post-viral Asthma

Monica A Thomas,Becky J Buelow,Amanda M Nevins,Stephanie E Jones,Francis C Peterson,Rebekah L Gundry,Mitchell H Grayson,Brian F Volkman

doi:10.1074/jbc.m114.627786

Monica A Thomas, Becky J Buelow + Show 6 more

Open Access

https://doi.org/10.1074/jbc.m114.627786

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Abstract

CCL28 is a human chemokine constitutively expressed by epithelial cells in diverse mucosal tissues and is known to attract a variety of immune cell types including T-cell subsets and eosinophils. Elevated levels of CCL28 have been found in the airways of individuals with asthma, and previous studies have indicated that CCL28 plays a vital role in the acute development of post-viral asthma. Our study builds on this, demonstrating that CCL28 is also important in the chronic post-viral asthma phenotype. In the absence of a viral infection, we also demonstrate that CCL28 is both necessary and sufficient for induction of asthma pathology. Additionally, we present the first effort aimed at elucidating the structural features of CCL28. Chemokines are defined by a conserved tertiary structure composed of a three-stranded β-sheet and a C-terminal α-helix constrained by two disulfide bonds. In addition to the four disulfide bond-forming cysteine residues that define the traditional chemokine fold, CCL28 possesses two additional cysteine residues that form a third disulfide bond. If all disulfide bonds are disrupted, recombinant human CCL28 is no longer able to drive mouse CD4+ T-cell chemotaxis or in vivo airway hyper-reactivity, indicating that the conserved chemokine fold is necessary for its biologic activity. Due to the intimate relationship between CCL28 and asthma pathology, it is clear that CCL28 presents a novel target for the development of alternative asthma therapeutics.

Highlights

CCL28 is associated with the pathogenesis of acute post-viral asthma
Tigate the importance of CCL28 in the development of chronic post-viral asthma pathology, we treated mice with an antiCCL28 mAb and found that it prevented the development of both mucous cell metaplasia (Fig. 1B) and airway hyper-reactivity (Fig. 1C) at day 49 PI Sendai virus (SeV). These findings indicate the critical importance of CCL28 in chronic post-viral asthma pathology and make CCL28 a potential target for the development of novel asthma therapeutics
In our mouse model we show that CCL28 is elevated at day 49 PI to a level above what is seen at day 21 PI

Summary

Introduction

CCL28 is associated with the pathogenesis of acute post-viral asthma. Significance: Inhibition of CCL28 presents a novel therapeutic option for the prevention of post-viral asthma. Elevated levels of CCL28 have been found in the airways of individuals with asthma, and previous studies have indicated that CCL28 plays a vital role in the acute development of postviral asthma. In the absence of a viral infection, we demonstrate that CCL28 is both necessary and sufficient for induction of asthma pathology. If all disulfide bonds are disrupted, recombinant human CCL28 is no longer able to drive mouse CD4؉ T-cell chemotaxis or in vivo airway hyper-reactivity, indicating that the conserved chemokine fold is necessary for its biologic activity. Due to the intimate relationship between CCL28 and asthma pathology, it is clear that CCL28 presents a novel target for the development of alternative asthma therapeutics

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