Abstract
BackgroundAirway epithelial cells and alveolar macrophages (AMs) are the first line of defense in the lung during infection. Toll-like receptor (TLR) agonists have been extensively used to define the regulation of inflammation in these cells. However, previous studies were performed in non-paired airway epithelial cells and AMs. The major goal of our study was to compare the pro- and anti-inflammatory responses of paired human primary airway epithelial cells and AMs to TLR3 and TLR4 agonists.MethodsTracheobronchial epithelial cells (TBEC) and AMs from four smokers and four non-smokers without lung disease were cultured with or without Poly(I:C) (PIC) (a TLR3 agonist) or LPS (a TLR4 agonist) for 4, 24 and 48 h. The immune responses of paired cells were compared.ResultsTBEC and AMs showed stronger pro-inflammatory cytokine (e.g., IL-8) responses to PIC and LPS, respectively. TLR3 and TLR4 mRNA levels were similar in non-stimulated TBEC and AMs. However, PIC stimulation in AMs led to sustained up-regulation of the immune negative regulators Tollip and A20, which may render AMs less sensitive to PIC stimulation than TBEC. Unlike AMs, TBEC did not increase NF-κB activation after LPS stimulation. Interestingly, smoking status was correlated with less TLR3 and IRAK-M expression in non-stimulated TBEC, but not in AMs. PIC-stimulated TBEC and LPS-stimulated AMs from smokers vs. non-smokers produced more IL-8. Finally, we show that expression of A20 and IRAK-M is strongly correlated in the two paired cell types.ConclusionsBy using paired airway epithelial cells and AMs, this study reveals how these two critical types of lung cells respond to viral and bacterial pathogen associated molecular patterns, and provides rationale for modulating immune negative regulators to prevent excessive lung inflammation during respiratory infection.
Highlights
Airway epithelial cells and alveolar macrophages (AMs) are the first line of defense in the lung during infection
Alveolar macrophages responded to both PIC and LPS by producing including CXCL8 (IL-8), but the induction of IL-8 was stronger after LPS at 24 and 48 h (P = 0.01) (Fig. 2d and e)
Differences in pathogen associated molecular patterns (PAMPs)-mediated induction of negative regulators in tracheobronchial epithelial cells (TBEC) To potentially explain the different pro-inflammatory responses to PIC and LPS in TBEC and macrophages, we examined the expression of Toll-interacting protein (Tollip), A20 and Interleukin-1 receptor-associated kinase 3 (IRAK-M), which are known to down-regulate TLR3 and TLR4 signaling pathways
Summary
Airway epithelial cells and alveolar macrophages (AMs) are the first line of defense in the lung during infection. Airway epithelial cells along with alveolar macrophages serve as the first line of host innate immune defense against airborne pathogens and other airborne environmental hazards [1] These lung cells are able to recognize pathogen associated molecular patterns (PAMPs) using receptors that include the Toll-like. Mubarak et al Respiratory Research (2018) 19:126 including Toll-interacting protein (Tollip), TNF alphainduced protein 3 or TNFAIP3 (A20) and interleukin-1 receptor-associated kinase 3 (IRAK-M). These negative regulators down-regulate the transcription and translation of TLR-induced genes during infection and inflammation [2]. Negative regulators of TLR signaling pathways have not been previously investigated in airway epithelial cells and alveolar macrophages from the same human subject (paired cells) to clarify their effect on inflammatory responses
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