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. 2019 Jul 12;11(13):4654-4671.
doi: 10.18632/aging.102077.

Ambient particulate matter attenuates Sirtuin1 and augments SREBP1-PIR axis to induce human pulmonary fibroblast inflammation: molecular mechanism of microenvironment associated with COPD

Chia-Ping Tien  1   2   3 , Chia-Hung Chen  4 , Wen-Yuan Lin  2   5   6 , Chiu-Shong Liu  2   5   6 , Ko-Jiunn Liu  7 , Michael Hsiao  3   8 , Yu-Chan Chang  3 , Shih-Chieh Hung  9   10   11
Affiliations

Ambient particulate matter attenuates Sirtuin1 and augments SREBP1-PIR axis to induce human pulmonary fibroblast inflammation: molecular mechanism of microenvironment associated with COPD

Chia-Ping Tien et al. Aging (Albany NY). .

Abstract

Evidences have shown a strong link between particulate matter (PM) and increased risk in human mortality and morbidity, including asthma, chronic obstructive pulmonary disease (COPD), respiratory infection, and lung cancer. However, the underlying toxicologic mechanisms remain largely unknown. Utilizing PM-treated human pulmonary fibroblasts (HPF) models, we analyzed gene expression microarray data and Ingenuity Pathway Analysis (IPA) to identify that the transcription factor sterol regulatory element-binding protein 1 (SREBP1) was the main downstream regulator of Sirtuin1 (SIRT1). Quantitative PCR and western blot results showed that SIRT1 inhibited SREBP1 and further downregulated Pirin (PIR) and Nod-like receptor protein 3 (NLRP3) inflammasome after PM exposure. Inhibitors of SIRT1, SREBP1, and PIR could reverse PM-induced inflammation. An in silico analysis revealed that PIR correlated with smoke exposure and early COPD. Immunohistochemical analysis of tissue microarrays from PM-fed mouse models was used to determine the association of PIR with PM. These data demonstrate that the SIRT1-SREBP1-PIR/ NLRP3 inflammasome axis may be associated with PM-induced adverse health issues. SIRT1 functions as a protector from PM exposure, whereas PIR acts as a predictor of PM-induced pulmonary disease. The SIRT1-SREBP1-PIR/ NLRP3 inflammasome axis may present several potential therapeutic targets for PM-related adverse health events.

Keywords: Pirin; SREBP1; Sirtuin1; inflammasomes; particulate matter.

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Conflict of interest statement

CONFLICTS OF INTEREST: The authors have no conflicts of interest to declare.

Figures

Figure 1
Figure 1
PM induced several potential transcription factors in a dose-dependent manner in normal lung cells. (A) The flowchart represents the procedure of microarray chips established in human pulmonary fibroblasts. (B) Detailed heatmaps highlight the significantly up- and down-regulated genes after PM treatment, that were normalized gene expression from the microarray database analysis. (C) The ranking of candidate transcription factors by IPA database of microarray from PM treatment compared with the sham group in human pulmonary fibroblasts. The cut-off was a 1.5-fold change.
Figure 2
Figure 2
Signatures regulated by PM in HPF models. (A) The mRNA level of SREBP1 after PM treatment. (B) The prediction of SREBP1-network derived from the common signature, by comparison of IPA database with microarray data from HPF cells with a 1.5-fold-change cut-off. The intensity of the node color indicates the degree of activating (orange) or inhibiting (blue) regulation following PM interaction. (C) Several mRNA levels of SREBP1 downstream factors, including PIR, LIF, IL-6, IL-24, and CXCL8, after PM treatment in HPF.
Figure 3
Figure 3
PM exposure is positively correlated with activation of the SREBP1-PIR signaling pathway through SIRT1 downregulation. (A) Western blot analysis of PIR after PM treatment in HPF. (B) PIR activity from cell culture supernatant in PM-induced models. (C) Levels of SREBP1, SIRT1, and PIR were measured from cell culture supernatant of PM-induced models. (D) mRNA levels of SREBP1 in PF429242-PM co-treated HPF models. (E) mRNA levels of PIR in PF429242-PM co-treated HPF models. (F) PIR activity from cell culture supernatant in PF429242-PM co-treated HPF models. (G) Western blot analysis of PIR and SIRT1 in TPh A-PM co-treated HPF models. (H) PIR activity from cell culture supernatant in TPh A-PM co-treated HPF models. (I) mRNA level of PIR in Ex527-PM co-treated HPF models. (J) Western blot analysis of SIRT1 and PIR in Ex527-PM co-treated HPF models. (K) Level of PIR was measured from cell culture supernatant in Ex527-PM co-treated HPF models.
Figure 4
Figure 4
NLRP3 inflammasome was upregulated by PM exposure. (A) mRNA level of NLRP3 after PM in HPF. (B) Western blot analysis of NLRP3 and IL-1β after PM in HPF. (C) mRNA level of NLRP3 in Ex527-PM co-treated HPF models. (D) mRNA levels of NLRP3 in PF429242-PM co-treated HPF models. (E) Western blot analysis of PIR, SREBP1, and NLRP3 in TPh A-PM co-treated HPF models.
Figure 5
Figure 5
Overexpression of PIR correlates with smoke and early COPD. (A) Detailed heatmap highlights the correlation between the mRNA expression level of PIR and smoke in the GSE4498 cohort (n = 22) using Oncomine online analysis tool. (B) Differential mRNA levels of PIR, FBG, and IL-6 between non-smoker and smoker in the GSE4498 cohort. (C) Detailed heatmaps highlight the correlation between the mRNA expression levels of PIR and non-smoker, smoker, COPD, and early COPD in the GSE5060 cohort (n = 38) using Oncomine online analysis tool. (D) Differential mRNA levels of PIR, FBG, and IL-6 in non-smoker, smoker, COPD, and early COPD in the GSE5060 cohort (n = 38) in the analysis by the Oncomine online analysis tool. (E) The immunohistochemical staining results showed PM-fed mice group had higher concentration of the PIR protein in the lung tissue.
Figure 6
Figure 6
A model illustrates that PM activates the SREBP1-PIR/inflammasomes signaling axis through SIRT1 -mediated modulation. (A) A schematic model to describe the positive feedback loop and detailed mechanisms of the SIRT1-SREBP1-PIR axis and crosstalk with NF-κB signaling. (B) SIRT1 modulates the SREBP1-PIR/NLRP3 inflammasome axis in response to PM. SIRT1 functions as a protector from PM exposure. The SIRT1-SREBP1-PIR/NLRP3 inflammasome axis may present an attractive therapeutic target for PM-related adverse health events.
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