Activation through toll‐like receptor 2 on group 2 innate lymphoid cells can induce asthmatic characteristics

Abstract

Background Type 2 innate lymphoid cells (ILC2s) are one of the sources of IL‐5 and IL‐13 in allergic airway inflammation. Innate immune receptors such as Toll‐like receptors (TLRs) expressed on epithelial cells could contribute to ILC2 activation through IL‐33 production, but a direct effect of TLRs on ILC2s remains to be elucidated. Objectives We hypothesized that TLRs can directly activate lung ILC2s and participate in the pathogenesis of asthma. Methods After intranasal administration of IL‐33 to wild‐type (WT), TLR2KO and TLR4KO female mice, ILC2s were isolated from harvested lungs. ILC2s were incubated with IL‐2 and TLR stimulants (pam3csk4 (PAM), house dust mite extract (HDM)). In some experiments, TLR2 or dectin‐1 signalling inhibitors were used. As an in vivo model, the mice were treated with IL‐33 and rested until lung recruitment of eosinophils regressed. Then they were treated intranasally with PAM + HDM or vehicle and analysed. Results In vitro stimulation of isolated ILC2s showed that PAM could induce IL‐13 and IL‐5 production, and HDM had a synergistic effect on this stimulation. Both effects were dependent on TLR2 and NF‐κB signalling. PAM + HDM stimulation of WT mice led to increased ILC2s, airway hyperresponsiveness and increased levels of both neutrophils and eosinophils in bronchoalveolar lavage fluid. These observations were dependent on TLR2. Conclusions & clinical relevance TLR2 can directly activate lung ILC2s, an effect that is augmented by HDM. Asthmatic characteristics mediated through the TLR2 pathway were evident in the in vivo mice model. These data implicate a new pathway of ILC2 activation in the pathogenesis of asthma.

TLR2-Melatonin Feedback Loop Regulates the Activation of NLRP3 Inflammasome in Murine Allergic Airway Inflammation

“…In line with these data, our present study demonstrated a significant increase of TLR2 expression in WT mice post OVA challenge, and this increase was accounted from its induced-expression on various cell types. Previous studies also indicate its wide spectral expression (35)(36)(37), and reports from our group and others have indicated that TLR2 on macrophages (38), group 2 innate lymphoid cells (39) and epithelial cells (40) may contribute to allergic airway inflammation. Furthermore, the increased expression of TLR2 was accompanied with lung inflammation exacerbation in WT mice post OVA challenge in this study.…”

“…When OVA, HDM, or Alternaria was given via inhalation or intranasally, each of them can be recognized and sensed by TLRs reportedly, especially TLR2 (40). Similarly, intranasally given IL-33 is reported can induce direct stimulation of TLR2 on ILC2s (39). However, papain, which is homologous of HDM-derived Der p1, activates innate immune responses in a manner distinct from that of PAPMs and can induce production of an alarmin IL-33 (63).…”

TLR9–IL-2 axis exacerbates allergic asthma by preventing IL-17A hyperproduction

“…Allergy, Inc. (Tokyo, Japan). The method for HDM-induced allergic asthma was optimized from our previous reports 9,56,57 .…”

“…The method for OVA-Alum-induced allergic asthma was used from our previous report 56 . C57BL/6N mice were sensitized intraperitoneally with 2 μg of ovalbumin from Sigma-Aldrich (OVA; A5503, Saint Louis, MO, USA) in conjunction with aluminum adjuvant in 0.5 mL of phosphate-buffered saline on days 0 and 14.…”

“…istration of HDM extract by using a flexiVent system (Scireq, Montreal, Quebec, Canada) 56 . The mice were tracheostomized while under anesthesia with ketamine (90 mg/kg) and medetomidine (1 mg/kg) administered via intraperitoneal injection.…”