Th2 cytokines impair innate immune responses to rhinovirus in respiratory epithelial cells

Abstract

(word count: 246245) 1Background: Asthma and other Th2 inflammatory conditions have been associated with increased 2 susceptibility to viral infections. The mechanisms by which Th2 cytokines can influence immune 3 responses to infections are largely unknown. 4 Methods:We measured the effects of Th2 cytokines (IL-4 and IL-13) on bronchial epithelial cell 5 innate immune antiviral responses by assessing interferon (IFN-β and IFN-λ1) induction following 6 rhinovirus (RV)-16 infection. We also investigated the modulatory effects of Th2 cytokines on 7 signalling pathways involved in the rhinovirus-induced interferon production and inflammatory 8 cascade including Toll-like receptor (TLR)-3, interferon-responsive factor (IRF)-3, and nuclear 9 factor (NF)-kB., i.e. key molecules and transcription factors involved in the rhinovirus-induced 10 interferon production and inflammatory cascade. Pharmacological and redox modulation by the 11 reducing agent N-acetylcysteine onof these pathways was also testedassessed. 12Results: Th2 cytokines impaired RV16-induced interferon production, increased rhinovirus 13 replication and impaired TLR3 expression in bronchial epithelial cells. These results were 14 replicated in vivo: we found increased IL-4 mRNA levels in nasal epithelial cells from nasal 15 brushing of atopic rhinitis patients and a parallel reduction of TLR3 expression and increased RV16 16 replication compared to non-atopic subjects. Mechanistically, Th2 cytokines impaired RV-16 17 induced activation of IRF3, but had no effects on RV16-induced NF-kB activation in bronchial 18 epithelial cell cultures. N-acetylcysteine and phosphoinositide 3-kinase (PI3k) inhibitor restored the 19 inhibitory effects of Th2 cytokines over RV-16 induced activation of IRF3 and production of IFNs. 20Conclusions: IL-4 and IL-13, through inhibition of TLR3 expression and oxidant-mediated 21 inhibition of signalling ), impair immune response to RV-16 infection. These data suggest 22 that Th2 conditions increase susceptibility to infections and identify a pharmacological 23 approachapproaches with potential to restore impaired immune response in these conditions. 24Page 3 of 63 Allergy 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 Asthma is a chronic disorder of the airways that is typically inflammatory in nature and 3 affects millions of children and adults (1). (1). 4Viral infections of the respiratory tract early in life are associated with an increased risk of 5 developing asthma later in life and are also the most frequent causes of asthma exacerbations in 6 both children and adults (2). Rhinoviruses are the respiratory virus type that is most frequently 7 detected during asthma exacerbations (3). The innate immune response is at the forefront of the 8 defence against respiratory infections. Impaired innate immune responses have been reported to be 9...

IFN Deficiency in Asthma Attacks. Is Restoring Toll-like Receptor-7 Expression a New Treatment Approach in Severe Asthma?

“…This study is consistent with other studies showing that Th2 cytokines and transforming growth factor-b are able to suppress rhinovirus-induced IFN production and augment virus replication in bronchial epithelial cells (17,18) and fibroblasts (19). These studies did not investigate nuclear SOCS1 expression, so the mechanism(s) through which Th2 cytokines/transforming growth factor-b suppressed IFN induction are not known.…”

Allergen-induced airway responses

“…First, the majority of asthmatics ( particularly those with childhood-onset asthma) are atopic [15], and studies of birth cohorts have demonstrated a greatly increased risk of diagnosed asthma and AHR in atopic children [16], particularly those sensitised to house dust mite (HDM), cats and dogs [17]. Second, the presence of airway allergic inflammation predisposes children to rhinovirus-induced recurrent wheezing and asthma exacerbations [18], and this interaction between allergic sensitisation and virus exposure predisposes to the development of asthma in childhood [19], possibly through an effect of type-2 cytokines (such as interleukin (IL)-4 and IL-13) on the innate immune responses to airway viral infection [20]. Third, seasonal asthma, associated with specific environmental allergen exposure, is a well-described clinical entity [21].…”

Stimulation of the RIG-I/MAVS Pathway by Polyinosinic:Polycytidylic Acid Upregulates IFN-β in Airway Epithelial Cells with Minimal Costimulation of IL-8

“…Some studies did not observe such IFN-b deficiency (4-7). Yet, others report either intrinsic impairment of the IFN-b response to respiratory viruses (6,(8)(9)(10)(11) or negative modulation of this response by pathologic factors associated with diseased airways (12)(13)(14)(15)(16). Importantly, stimulation of IFN-b production or exogenous supplementation of this cytokine facilitates virus clearance even in cells with normal IFN-b responses (5,17,18).…”