Non-essential role for TLR2 and its signaling adaptor Mal/TIRAP in preserving normal lung architecture in mice

Saleela Madhavi Ruwanpura, Louise McLeod, Andrew Lilja, Gavin De Carle Brooks, Lovisa Dousha, Huei Jiunn Seow, Steven Bozinovski, Ross Vlahos, Paul John Hertzog, Gary Anderson, Brendan John Jenkins

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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.
Original languageEnglish
Article numbere78095
Number of pages9
JournalPLoS ONE
Volume8
Issue number10
DOIs
Publication statusPublished - 2013

Cite this

Ruwanpura, Saleela Madhavi ; McLeod, Louise ; Lilja, Andrew ; Brooks, Gavin De Carle ; Dousha, Lovisa ; Seow, Huei Jiunn ; Bozinovski, Steven ; Vlahos, Ross ; Hertzog, Paul John ; Anderson, Gary ; Jenkins, Brendan John. / Non-essential role for TLR2 and its signaling adaptor Mal/TIRAP in preserving normal lung architecture in mice. In: PLoS ONE. 2013 ; Vol. 8, No. 10.
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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.",
author = "Ruwanpura, {Saleela Madhavi} and Louise McLeod and Andrew Lilja and Brooks, {Gavin De Carle} and Lovisa Dousha and Seow, {Huei Jiunn} and Steven Bozinovski and Ross Vlahos and Hertzog, {Paul John} and Gary Anderson and Jenkins, {Brendan John}",
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Non-essential role for TLR2 and its signaling adaptor Mal/TIRAP in preserving normal lung architecture in mice. / Ruwanpura, Saleela Madhavi; McLeod, Louise; Lilja, Andrew; Brooks, Gavin De Carle; Dousha, Lovisa; Seow, Huei Jiunn; Bozinovski, Steven; Vlahos, Ross; Hertzog, Paul John; Anderson, Gary; Jenkins, Brendan John.

In: PLoS ONE, Vol. 8, No. 10, e78095, 2013.

Research output: Contribution to journalArticleResearchpeer-review

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T1 - Non-essential role for TLR2 and its signaling adaptor Mal/TIRAP in preserving normal lung architecture in mice

AU - Ruwanpura, Saleela Madhavi

AU - McLeod, Louise

AU - Lilja, Andrew

AU - Brooks, Gavin De Carle

AU - Dousha, Lovisa

AU - Seow, Huei Jiunn

AU - Bozinovski, Steven

AU - Vlahos, Ross

AU - Hertzog, Paul John

AU - Anderson, Gary

AU - Jenkins, Brendan John

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AB - 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.

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