Abstract
Myeloid differentiation factor 88 (MyD88) and MyD88-adaptor like (Mal)/Toll-interleukin 1 receptor domain containing adaptor protein (TIRAP) play a critical role in transducing signals downstream of the Toll-like receptor (TLR) family. While genetic ablation of the TLR4/MyD88 signaling axis in mice leads to pulmonary cell death and oxidative stress culminating in emphysema, the involvement of Mal, as well as TLR2 which like TLR4 also signals via MyD88 and Mal, in the pathogenesis of emphysema has not been studied. By employing an in vivo genetic approach, we reveal here that unlike the spontaneous pulmonary emphysema which developed in Tlr4−/− mice by 6 months of age, the lungs of Tlr2−/− mice showed no physiological or morphological signs of emphysema. A more detailed comparative analysis of the lungs from these mice confirmed that elevated oxidative protein carbonylation levels and increased numbers of alveolar cell apoptosis were only detected in Tlr4−/− mice, along with up-regulation of NADPH oxidase 3 (Nox3) mRNA expression. With respect to Mal, the architecture of the lungs of Mal−/− mice was normal. However, despite normal oxidative protein carbonylation levels in the lungs of emphysema-free Mal−/− mice, these mice displayed increased levels of apoptosis comparable to those observed in emphysematous Tlr4−/− mice. In conclusion, our data provide in vivo evidence for the non-essential role for TLR2, unlike the related TLR4, in maintaining the normal architecture of the lung. In addition, we reveal that Mal differentially facilitates the anti-apoptotic, but not oxidant suppressive, activities of TLR4 in the lung, both of which appear to be essential for TLR4 to prevent the onset of emphysema.
Highlights
Emphysema is a major component of the debilitating chronic obstructive pulmonary disease (COPD), the fifth most common cause of death world-wide [1]
We provide definitive genetic proof that MyD88-adaptor like (Mal) is not required for the function of TLR4 in protecting against the onset of emphysema
Since it has been shown that Myeloid differentiation factor 88 (MyD88) is required to prevent the onset of emphysema [3], these observations reveal a differential requirement for Mal and MyD88 in maintaining normal lung architecture via TLR4 signaling
Summary
Emphysema is a major component of the debilitating chronic obstructive pulmonary disease (COPD), the fifth most common cause of death world-wide [1]. While cigarette smoke (CS) exposure is the primary risk factor for COPD, only 10–20% of heavy smokers develop clinically-significant emphysema, and approximately 20% of patients with emphysema are non-smokers [2]. These observations suggest that factors intrinsic to the host (i.e. of genetic origin) are likely to determine an individual’s susceptibility to emphysema. Since CS is a rich source of oxidants, the molecular mechanisms regulating the balance between oxidant and anti-oxidant production in the lung have long been thought to be critical in promoting emphysema In this regard, an association between the regulation of oxidative stress by the innate immune system, and its role in emphysema, has recently emerged. The downstream signaling pathway(s) by which TLR4 regulates pulmonary oxidative stress levels and protects against emphysematous changes in the lung are not fully understood
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