Editorial - Journal of Pulmonology and Clinical Research (2017) Volume 1, Issue 1
Significance of IL-15 in asthma pathogenesisSathisha Upparahalli Venkateshaiah*
Department of Medicine, Tulane University, New Orleans, USA
- *Corresponding Author:
- Sathisha Upparahalli Venkateshaiah
Department of Medicine
E-mail: [email protected]
Accepted Date: October 10, 2017
Citation: Venkateshaiah SU. Significance of IL-15 in asthma pathogenesis. J Pulmonol Clin Res. 2017;1(1):1-3.
Immune-based diseases that are rising in prevalence jeopardize the health of the western world from the last decade [1,2]. In developing world 358 million people globally had asthma, 1990 . A chronic inflammatory pulmonary disorder responsible for over 397,100 deaths in 2015 . Asthma is one of these immune based chronic, inflammatory lung diseases characterized by variable airway obstruction, hyper responsiveness and remodelling [5-7]. Experimental research in the asthma field has largely focused on analysis of the cellular and molecular events induced by allergen exposure in sensitized animals and humans [8-12]. These research studies have been identified elevated production of IgE, mucus hyper secretion, and eosinophilic inflammation, which lead to lung function abnormalities and airway fibrosis [13-17]. Lung function abnormalities develop in chronic asthma disease and other chronic inflammatory processes on subsequent exposure to environmental inhalants such as allergens, organic and inorganic dusts, or autoimmune disease and sarcoidosis [18-23].
Immune-based diseases that are rising in prevalence jeopardize the health of the western world from the last decade [1,2]. In developing world 358 million people globally had asthma, 1990 . A chronic inflammatory pulmonary disorder responsible for over 397,100 deaths in 2015 . Asthma is one of these immune based chronic, inflammatory lung diseases characterized by variable airway obstruction, hyper responsiveness and remodelling [5-7]. Experimental research in the asthma field has largely focused on analysis of the cellular and molecular events induced by allergen exposure in sensitized animals and humans [8-12]. These research studies have been identified elevated production of IgE, mucus hyper secretion, and eosinophilic inflammation, which lead to lung function abnormalities and airway fibrosis [13-17]. Lung function abnormalities develop in chronic asthma disease and other chronic inflammatory processes on subsequent exposure to environmental inhalants such as allergens, organic and inorganic dusts, or autoimmune disease and sarcoidosis [18-23]. Antigen presenting cells (APCs) interact with and activate T cell subsets and initiate a series of immunological responses to develop airway disease. The airway inflammatory response in asthma is characterized by induced expression of multiple genes encoding cytokines, chemokines, and adhesion molecules, which are associated with recruitment of eosinophil’s and Th2 lymphocytes . These elevated levels of chemokines and cytokines are thought to be central regulators of many of the hallmark features of airway pathology including inflammation and airway hyperactivity [25-27]. In addition to the characteristic Th2 and Th3 mediated inflammatory response found in the airway during acute asthma episodes, chronic asthma is characterized by structural changes that are termed airway remodelling [24-28]. Remodellingassociated changes in the airway include peribronchial fibrosis with increased deposition of collagen (types I, III, and V), smooth muscle hypertrophy/hyperplasia, and mucus secretion. Repeated cycles of inflammation and repair in the airway in chronic asthma are considered to be the driving force for airway remodelling. Therefore, a great need to continue with innovative fundamental studies to uncover new possibilities for the therapeutic interventions for airway hyperactivity/obstruction and fibrosis. Currently, anti-inflammatory corticosteroid inhalers and other medications are available to treat airway inflammation and obstruction. These treatments show a significant reduction in inflammation; but fail to restrict or reverse the progression of the bronchial airway obstruction and fibrosis.
IL-15 is important in linking innate and adaptive antiviral immune responses, promoting natural killer (NK), Υδ T cells and memory CD8 T cell mediated anti-viral immune responses [29-31]. It is expressed by a large number of cell types including NK cells, Number of T cells, intestinal epithelial cells, monocytes, macrophages, and dendritic cells (DC). A significantly increased IL-15 is detected in steroid-treated patients asthmatics compared to non-steroid treated asthmatics . Importantly, muscle and serum IL-15 protein levels decline progressively with advanced age is reported in mice . Additionally, age-related decline in expression of mRNA coding for the “sushi-only” isoform of sIL-15Rα was also observed, which indicates reduced IL-15 secretion and stability with aging in mice. Furthermore, IL-15 polymorphism and IL-15 deficiency is reported in pediatric asthma pathogenesis [34,35]. Still, IL-15’s role is yet not clearly understood in asthma pathogenesis. Based on these reports suggest that IL-15 deficiency may be critical in promoting asthma pathogenesis; therefore, our current study tested the hypothesis whether IL-15 overexpression protect asthma pathogenesis including airway hyper responsiveness, resistance and compliance . We have found in our experimental model validated that indeed endogenous deficiency of IL-15 promotes baseline airway resistance, which is rescued in same endogenous IL-15 deficient mice following rIL-15 treatment. Further, we provide evidence that rIL-15 treatment in allergen induced asthma model diminishes allergen-induced airway obstruction and improves airway compliance down regulate pro-inflammatory cytokines and mucus producing goblet cell hyperplasia in the lung compared to the controls. Furthermore, we validated a rIL- 15 pre-treatment finding that improves allergen induced airway obstruction, reduced proinflamatory cytokine and goblet cell hyperplasia using the asthmatic IL-15 overexpressed mice. We also show that human IL-15 agonist treatment to asthmatic mice down regulates most of the characteristic features that includes airway obstruction and compliance. This indicates that IL-15 agonist will be a possible novel future therapeutic strategy for non-steroidal treatment of asthmatics. Lastly, we provide mechanistic pathway operational in IL-15 induced protection of asthma pathogenesis indicates that STAT5 regulate IL-15 induced regulatory T cells induction and activation that induces the levels of IFN-Ƴ and regulatory T cell induced IL-10. We believe our approach will provide a novel therapeutic molecule to restrict or reverse the progression of airway hyperactivity and bronchial fibrosis in asthma.
- ISAAC worldwide variation in prevalence of symptoms of asthma allergic rhino conjunctivitis and atopic eczema. The International Study of Asthma and Allergies in Childhood (ISAAC) Steering Committee Lancet. 1998; 351(9111):1225-32.
- Broide DH. Molecular and cellular mechanisms of allergic disease. The Journal of Allergy and Clinical Immunology. 2001;108(2):65-71.
- Disease GBD Injury I & Prevalence C Global regional and national incidence prevalence and years lived with disability for 310 diseases and injuries. 1990-2015 a systematic analysis for the Global Burden of Disease Study Lancet. 2016;388(10053):1545-1602.
- Mortality GBD & Causes of Death C Global regional and national life expectancy all-cause mortality and cause specific mortality for 249 causes of death. 1980-2015 a systematic analysis for the Global Burden of Disease Study Lancet. 2015;388(10053):1459-1544.
- Skloot G, Permutt S, Togias A. Airway hyper responsiveness in asthma a problem of limited smooth muscle relaxation with inspiration. The Journal of Clinical Investigation. 1995;96(5):2393-2403.
- Postma DS, Kerstjens HA. Characteristics of airway hyper responsiveness in asthma and chronic obstructive pulmonary disease. American Journal of Respiratory and Critical Care Medicine. 1995;158(5):187-192.
- Bousquet J, Jeffery PK, Busse WW, et al. Asthma. From bronchoconstriction to airways inflammation and remodeling. American Journal of Respiratory and Critical Care Medicine. 2000;161(5):1720-1745.
- Abbas AR. Lung gene expression in a rhesus allergic asthma model correlates with physiologic parameters of disease and exhibits common and distinct pathways with human asthma and a mouse asthma model. The American Journal of Pathology. 2011;179(4):1667-80.
- Abraham WM. Of mice and men. American Journal of Respiratory Cell and Molecular Biology. 2003;28(1):1-4.
- Afshar R, Medoff BD, Luster AD. Allergic asthma a tale of many T cells Clinical and experimental allergy. Journal of the British Society for Allergy and Clinical Immunology. 2008;38(12):1847-57.
- Ahmad T, Mabalirajan U, Hasija K, et al. Mepacrine treatment attenuates allergic airway remodeling segregated from airway inflammation in mice. International Immunopharmacology. 2011;11(1):74-8.
- Al Heialy S, McGovern TK, Martin JG. Insights into asthmatic airway remodeling through murine models. Respirology. 2011;16(4):589-97.
- Agrawal DK, Shao Z. Pathogenesis of allergic airway inflammation. Current Allergy and Asthma Reports. 2010;10(1):39-48.
- Ahluwalia SK. Mouse allergen is the major allergen of public health relevance in Baltimore City. The Journal of Allergy and Clinical Immunology. 2013;132(4):830-35.
- Al-Muhsen S, Johnson JR, Hamid Q. Remodeling in asthma. The Journal of Allergy and Clinical Immunology. 2011;128(3):451-62.
- Akuthota P, Xenakis JJ, Weller PF. Eosinophils offenders or general bystanders in allergic airway disease and pulmonary immunity. Journal of Innate Immunity. 2011;3(2):113-19.
- Araujo LM. Exacerbated Th2-mediated airway inflammation and hyper responsiveness in autoimmune diabetes prone NOD mice a critical role for CD1d-dependent NKT cells. European Journal of Immunology. 2010;34(2):327-35.
- Jeffery PK. Remodeling in asthma and chronic obstructive lung disease. American Journal of Respiratory and Critical Care Medicine. 2001;164(10):28-38.
- Du Bois RM. Idiopathic pulmonary fibrosis present understanding and future options. European respiratory review an official. Journal of the European Respiratory Society. 2011;20(121):132-33.
- Naik PK. Periostin promotes fibrosis and predicts progression in patients with idiopathic pulmonary fibrosis. American journal of physiology. Lung Cellular and Molecular Physiology. 2011;303(12):1046-56.
- Zolak JS, de Andrade JA. Idiopathic pulmonary fibrosis. Immunology and Allergy Clinics of North America. 2012;32(4):473-85.
- Wells AU, Kelleher WP. Idiopathic pulmonary fibrosis pathogenesis and novel approaches to immunomodulation we must not be tyrannized by the Panther data. American Journal of Respiratory and Critical Care Medicine. 2013;187(7):677-79.
- Phillips JE. Bleomycin induced lung fibrosis increases work of breathing in the mouse. Pulmonary Pharmacology & Therapeutics. 2012;25(4):281-85.
- Cohn L, Elias JA, Chupp GL. Asthma mechanisms of disease persistence and progression. Annu Rev Immunol. 2004;22:789-815.
- Wills-Karp M. Interleukin-13 central mediator of allergic asthma. Science. 2008;282(5397):2258-61.
- Bochner BS, Undem BJ, Lichtenstein LM. Immunological aspects of allergic asthma. Annu Rev Immunol. 1994;12:295-335.
- Wills-Karp M. IL-12/IL-13 axis in allergic asthma. The Journal of Allergy and Clinical Immunology. 2001;107(1):9-18.
- Davies DE, Wicks J, Powell RM, et al. Airway remodeling in asthma new insights. The Journal of Allergy and Clinical Immunology. 2003;111(2):215-225.
- Carson WE. Endogenous production of interleukin 15 by activated human monocytes is critical for optimal production of interferon-gamma by natural killer cells in vitro. The Journal of Clinical Investigation. 1995;96(6):2578-82.
- Fawaz LM, Sharif-Askari E, Menezes J. Up-regulation of NK cytotoxic activity via IL-15 induction by different viruses a comparative study. Journal of Immunology. 1999;163(8):4473-80.
- Weng NP, Liu K, Catalfamo M, et al. IL-15 is a growth factor and an activator of CD8 memory T cells. Annals of the New York Academy of Sciences. 2002;975:46-56.
- Komai Koma M. Immuno-regulatory cytokines in asthma IL-15 and IL-13 in induced sputum. Clinical and experimental allergy journal of the British Society for Allergy and Clinical Immunology. 2001;31(9):1441-48.
- Quinn LS, Anderson BG, Strait-Bodey L, et al. Serum and muscle interleukin-15 levels decrease in aging mice correlation with declines in soluble interleukin-15 receptor alpha expression. Experimental Gerontology. 2010;45(2):106-112.
- Stanca VL. The Role of IL-15 Deficiency in the Pathogenesis of Virus-Induced Asthma Exacerbations. PLoS Pathog. 2011;8(4):1-10.
- Bierbaum S. Confirmation of association of IL-15 with pediatric asthma and comparison of different controls. Allergy. 2006;61(5):576-80.
- Venkateshaiah SU. Regulatory effects of IL-15 on allergen-induced airway obstruction. The Journal of Allergy and Clinical Immunology. 2017.