Viral-induced asthma exacerbations, which exhibit both Th1-type neutrophilia and Th2-type inflammation, associate with secretion of Interleukin (IL)-1β. IL-1β induces neutrophilic inflammation. It ...may also increase Th2-type cytokine expression. We hypothesised that IL-1β is causally involved in both Th1 and Th2 features of asthma exacerbations. This hypothesis is tested in our mouse model of viral stimulus-induced asthma exacerbation.
Wild-type (WT) and IL-1β deficient (IL-1β
) mice received house dust mite (HDM) or saline intranasally during three weeks followed by intranasal dsRNA (PolyI:C molecule known for its rhinovirus infection mimic) for three consecutive days to provoke exacerbation. Bronchoalveolar lavage fluid was analysed for inflammatory cells and total protein. Lung tissues were stained for neutrophilic inflammation and IL-33. Tissue homogenates were analysed for mRNA expression of Muc5ac, CXCL1/KC, TNF-α, CCL5, IL-25, TSLP, IL-33, IL-1β, CCL11 and CCL2 using RT-qPCR.
Expression of IL-1β, neutrophil chemoattractants, CXCL1 and CCL5, the Th2-upstream cytokine IL-33, and Muc5ac were induced at exacerbation in WT mice and were significantly inhibited in IL-1β
mice at exacerbation. Effects of HDM alone were not reduced in IL-1β-deficient mice.
Without being involved in the baseline HDM-induced allergic asthma, IL-1β signalling was required to induce neutrophil chemotactic factors, IL-33, and Muc5ac expression at viral stimulus-induced exacerbation. We suggest that IL-1β has a role both in neutrophilic and Th2 inflammation at viral-induced asthma exacerbations.
Factors such as tracer concentration, mucociliary clearance, exposed airway surface area, and exposure time were controlled in the nasal experiments, supporting their specificity.5 A defect ...epithelial barrier may transiently occur in acute disease conditions6 but may not be a basic feature of asthma and allergic rhinitis....alpha2-macroglobulin along with albumin in bronchial surface liquids indicate the occurrence of plasma exudation in allergen-exposed patients with asthma (see references cited in Persson and Uller7).The defect barrier paradigm is built on in vitro observations.2 However, progress in understanding molecular-biological-functional aspects of epithelial cells in culture may not quite have the purported bearing on our understanding of barrier functions in allergic airways in vivo. 1 S. Löser, L.G. Gregory, Y. Zhang, K. Schaefer, S.A. Walker, J. Buckley, Pulmonary ORMDL3 is critical for induction of Alternaria-induced allergic airways disease, J Allergy Clin Immunol, Vol. 139, 2017, 1496-1507.e3 2 S.N. Georas, F. Rezaee, Epithelial barrier function: at the front of asthma immunology and allergic airway inflammation, J Allergy Clin Immunol, Vol. 134, 2014, 509-520 3 R.K. Elwood, S. Kennedy, A. Belzberg, J.C. Hogg, P.D. Paré, Respiratory mucosal permeability in asthma, Am Rev Respir Dis, Vol. 129, 1983, 523-527 4 M.D. Donno, A. Chetta, A. Foresi, G. Gavaruzzi, G. Ugolotti, D. Olivieri, Lung epithelial permeability and bronchial responsiveness in subjects with stable asthma, Chest, Vol. 111, 1997, 1255-1260 5 L. Greiff, M. Andersson, C. Svensson, S. Lundin, P. Wollmer, C.G.A. Persson, Reduced airway absorption in seasonal allergic rhinitis, Am J Respir Crit Care Med, Vol. 156, 1997, 783-786 6 P. Lemarchand, T. Chinet, M.A. Collignon, G. Urzua, L. Barritault, G.J. Huchon, Bronchial clearance of DTPA is increased in acute asthma but not in chronic asthma, Am Rev Respir Dis, Vol. 145, 1992, 147-152 7 C. Persson, L. Uller, Roles of plasma exudation in asthma and COPD, Clin Exp Allergy, Vol. 39, 2009, 1626-1629
Abstract
There is a link between high lipopolysaccharide (LPS) levels in the blood and the metabolic syndrome, and metabolic syndrome predisposes patients to severe COVID-19. Here, we define an ...interaction between SARS-CoV-2 spike (S) protein and LPS, leading to aggravated inflammation in vitro and in vivo. Native gel electrophoresis demonstrated that SARS-CoV-2 S protein binds to LPS. Microscale thermophoresis yielded a KD of ∼47 nM for the interaction. Computational modeling and all-atom molecular dynamics simulations further substantiated the experimental results, identifying a main LPS-binding site in SARS-CoV-2 S protein. S protein, when combined with low levels of LPS, boosted nuclear factor-kappa B (NF-κB) activation in monocytic THP-1 cells and cytokine responses in human blood and peripheral blood mononuclear cells, respectively. The in vitro inflammatory response was further validated by employing NF-κB reporter mice and in vivo bioimaging. Dynamic light scattering, transmission electron microscopy, and LPS-FITC analyses demonstrated that S protein modulated the aggregation state of LPS, providing a molecular explanation for the observed boosting effect. Taken together, our results provide an interesting molecular link between excessive inflammation during infection with SARS-CoV-2 and comorbidities involving increased levels of bacterial endotoxins.
Macrophages play an important role in asthma pathogenesis both in the inflammatory and resolution phase of the disease. Macrophages can acquire different polarisation states dependent on their ...microenvironment. It is yet unclear through which mechanism the microenvironment affects the anti-viral response in macrophages. We hypothesized that the macrophage microenvironment regulates rhinovirus-induced IFNβ expression. Murine bone marrow-derived monocytes and human differentiated THP-1 cells were stimulated with M-CSF or GM-CSF and IFNγ or IL-4/IL-13, respectively, to mimic a Th1 or Th2 environment. Macrophages were infected with rhinovirus and gene and protein levels of IFNβ and pattern recognition receptor expression were measured. In subsequent experiments an IκB kinase inhibitor was used to study the involvement of NFκB. Both murine and human M1-like macrophages exhibited higher levels of IFNβ and pattern recognition receptors after rhinovirus infection than M2-like macrophages. Blockage of NFκB resulted in a lower expression of rhinovirus-induced IFNβ in human M1-like macrophages while inducing a higher expression in M2-like macrophages, suggesting that the interferon response towards viral infection was mediated by NFκB. These findings could contribute to a better understanding of mechanisms causing reduced anti-viral responses at viral-induced exacerbations in asthma.
...to discover treatments that are improvements over antiasthma corticosteroids, novel molecular targets are of interest.1,6,7 With ensuing drug candidates, effects on both bronchial wall and lumen ...indices of inflammation would need attention as would the little understood balance between inhibition of disease-driving inflammation and effects on protective innate immunity.
COPD and asthma exacerbations are commonly triggered by rhinovirus infection. Potentially promoting exacerbations, impaired anti-viral signaling and attenuated viral clearance have been observed in ...diseased bronchial epithelium. Oxidative stress is a feature of inflammation in asthma and COPD and is prominent during exacerbations. It is not known whether oxidative stress affects the anti-viral signaling capacity. Bronchial epithelial cells from asthmatic and COPD donors were infected with rhinovirus or treated with the oxidative stressor H
O
followed by exposure to the synthetic viral replication intermediate poly(I:C). Poly(I:C) was used to ascertain a constant infection-like burden. Gene and protein levels of antioxidants as well as anti-viral responses were measured 3 and 24 h post poly(I:C) exposure. Rhinovirus infection and poly(I:C) stimulation induced protein levels of the antioxidants SOD1 and SOD2. In asthmatic bronchial epithelial cells pre-treatment with H
O
dose-dependently decreased the antioxidant response to poly(I:C), suggesting exaggerated oxidative stress. Further, poly(I:C)-induced IFNβ gene expression was reduced after pre-treatment with H
O
. This epithelial effect was associated with a reduced expression of the pattern recognition receptors RIG-I, MDA5 and TLR3 both on gene and protein level. Pre-treatment with H
O
did not alter antioxidant responses in COPD bronchial epithelial cells and, more modestly than in asthma, reduced poly(I:C)-induced IFNβ gene expression. Knockdown of TLR3 but not RIG-I/MDA5 abrogated impairment of poly(I:C)-induced IFNβ gene expression by H
O
. We developed a method by which we could demonstrate that oxidative stress impairs anti-viral signaling in bronchial epithelial cells from asthmatic and COPD patients, most pronounced in asthma. The impairment apparently reflects reduced responsiveness of TLR3. These present findings shed light on molecular mechanisms potentially causing reduced interferon responses to rhinovirus infection at exacerbations in asthma and COPD. Together, our findings suggest a possible self-perpetuating vicious cycle underlying recurrent exacerbations, leading to an impaired anti-viral response, which in turn leads to viral-induced exacerbations, causing more airway inflammation.
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