Targeting IL-1β and IL-17A Driven Inflammation during Influenza-Induced Exacerbations of Chronic Lung Inflammation

Abstract

For patients with chronic lung diseases, such as chronic obstructive pulmonary disease (COPD), exacerbations are life-threatening events causing acute respiratory distress that can even lead to hospitalization and death. Although a great deal of effort has been put into research of exacerbations and potential treatment options, the exact underlying mechanisms are yet to be deciphered and no therapy that effectively targets the excessive inflammation is available. In this study, we report that interleukin-1β (IL-1β) and interleukin-17A (IL-17A) are key mediators of neutrophilic inflammation in influenza-induced exacerbations of chronic lung inflammation. Using a mouse model of disease, our data shows a role for IL-1β in mediating lung dysfunction, and in driving neutrophilic inflammation during the whole phase of viral infection. We further report a role for IL-17A as a mediator of IL-1β induced neutrophilia at early time points during influenza-induced exacerbations. Blocking of IL-17A or IL-1 resulted in a significant abrogation of neutrophil recruitment to the airways in the initial phase of infection or at the peak of viral replication, respectively. Therefore, IL-17A and IL-1β are potential targets for therapeutic treatment of viral exacerbations of chronic lung inflammation

IL-1β is a key cytokine that induces trypsin upregulation in the influenza virus–cytokine–trypsin cycle

“…The effects of cytokine synergism have been reported in various host cellular responses. Synergistic effects of IL-1b, IL-6 and TNF-a on inflammatory and stress mediators [22] and IL-1b and IL-17 on chronic lung inflammation after viral infection [23] have been reported. In particular, the interaction between IL-1b and IL-6 in many types of inflammation [24][25][26] and the mechanisms of synergism [27][28][29] have been studied extensively.…”

“…The mice were treated according to the Guide for the Care and Use of Laboratory Animals (NIH Publication No. 85- 23,1996), and the study was approved by the Animal Care Committee of Tokushima University. Influenza virus A/Puerto Rico/8/ 34 (H1N1) (PR8) was kindly provided by The Research Foundation for Microbial Diseases of Osaka University (Kagawa, Japan).…”

“…The effects of challenges with individual and multiple pro-inflammatory cytokines on the inflammatory responses in various organs have been reported not only in mice and rats [22][23][24][25] but also in various cell lines [26][27][28][29][30][31]. These studies highlighted the interactions between IL-1b, IL-6 and TNF-a, which contribute to disease progression.…”

The anti-viral facet of anti-rheumatic drugs: Lessons from COVID-19

“…Authors reported that IL-1β mediates virus-induced M2 muscarinic receptor dysfunction and airway hyper-reactivity during parainfluenza virus infection [218]. Data from the literature reported that IL-1β and IL-17A are key mediators of neutrophilic inflammation in influenzainduced exacerbations of chronic lung inflammation [219].…”

Molecular and clinical diseasome of comorbidities in exacerbated COPD patients

“…Interleukin-1β, angiotensin converting enzyme-1 and endothelin-1 genes were associated with more than 45% of these shared links (table 2), supporting the role of inflammation and vascular physiology as specific mechanisms underlying the pathobiology of comorbidities in COPD. Furthermore, these three genes have also been related with the pathogenesis of COPD [28][29][30][31][32][33][34], hence providing a link between comorbidities and COPD itself, as recently suggested by a model of COPD that identifies the lung, the bone marrow and the adipose tissue as a vascularly interconnected network of potential pathogenic relevance [35]. In this context, it is of note that the diseasome (clinical or molecular diseasome) presented here has a very prominent "vascular" component, which may reflect the fact that admissions for exacerbation of COPD can also have a significant cardiovascular component [36,37].…”