PARP-1 inhibition provides protection against elastase-induced emphysema by mitigating the expression of matrix metalloproteinases

Dharwal, Vivek; Sandhir, Rajat; Naura, Amarjit S.

doi:10.1007/s11010-019-03510-1

Cited by 18 publications

(11 citation statements)

References 45 publications

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“…Likewise, we reported previously that PJ34 (a PARP1 inhibitor) significantly improved the mitochondrial biogenesis and antioxidant capacity in the heart tissues of T. cruziinfected mice and genetic deletion of PARP1 decreased the collagen deposition and the cardiac fibrosis and remodeling in chronically infected mice (49). Others have shown that treatment with olaparib (PARP1 inhibitor) ameliorated MMP2 and MMP9 expression in an elastase-induced mouse model of emphysema (50). Thus, based on our previous and present findings, we surmise that PARP1 plays an important role in progression of inflammation and fibrosis in CD through the engagement of cGAS-NF-B and AP-1 signaling pathways.…”

Section: Discussionmentioning

confidence: 59%

Trypanosoma cruzi Induces the PARP1/AP-1 Pathway for Upregulation of Metalloproteinases and Transforming Growth Factor β in Macrophages: Role in Cardiac Fibroblast Differentiation and Fibrosis in Chagas Disease

Choudhuri

Garg

2020

mBio

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Chagas disease (CD), caused by Trypanosoma cruzi, is a degenerative heart condition. In the present study, we investigated the role of poly [ADP-ribose] polymerase 1/activator protein 1 (PARP1/AP-1) in upregulation of profibrotic macrophages (Mϕ) and subsequent development of cardiac fibrosis in CD. We used in vitro and in vivo models of T. cruzi infection and chemical and genetic inhibition of Parp1 to examine the molecular mechanisms by which Mϕ might augment profibrotic events in CD. Cultured (RAW 264.7 and THP-1) Mϕ infected with T. cruzi and primary cardiac and splenic Mϕ of chronically infected mice exhibited a significant increase in the expression, activity, and release of metalloproteinases (MMP2, MMP9, and MMP12) and the cytokine transforming growth factor β (TGF-β). Mϕ release of MMPs and TGF-β signaled the cardiac fibroblast to myofibroblast differentiation, as evidenced by a shift from S100A4 to alpha smooth muscle actin (α-SMA) expression. Incubation of infected Mϕ with MMP2 and MMP9 inhibitors resulted in 60 to 74% decline in TGF-β release, and MMP9 and PARP1 inhibitors resulted in 57 to 70% decline in Mϕ TGF-β-driven cardiac fibroblast differentiation. Likewise, histological studies showed a 12- to 16-fold increase in myocardial expression of CD68 (Mϕ marker) and its colocalization with MMP9/TGF-β, galectin-3, and vimentin in wild-type mice with CD. In comparison, chronically infected Parp1−/− mice exhibited a >50% decline in myocardial levels of Mϕ and associated fibrosis markers. Further study showed that PARP1 synergized with c-Fos and JunB AP-1 family members for transcriptional activation of profibrotic response after T. cruzi infection. We conclude that PARP1 inhibition offers a potential therapy for controlling the T. cruzi-driven fibroblast differentiation in CD through modulation of the Mϕ signaling of the AP-1–MMP9–TGF-β pathway. IMPORTANCE Cardiomyopathy is the most important clinical manifestation of T. cruzi-driven CD. Recent studies have suggested the detrimental role of the matrix metalloproteinases MMP2 and MMP9 in extracellular matrix (ECM) degradation during cardiac remodeling in T. cruzi infection. Peripheral TGF-β levels are increased in clinically symptomatic CD patients over those in clinically asymptomatic seropositive individuals. We provide the first evidence that during T. cruzi infection, Mϕ release of MMP2 and MMP9 plays an active role in activation of TGF-β signaling of ECM remodeling and cardiac fibroblast-to-myofibroblast differentiation. We also determined that PARP1 signals c-Fos- and JunB-mediated AP-1 transcriptional activation of profibrotic gene expression and demonstrated the significance of PARP1 inhibition in controlling chronic fibrosis in Chagas disease. Our study provides a promising therapeutic approach for controlling T. cruzi-driven fibroblast differentiation in CD by PARP1 inhibitors through modulation of the Mϕ signaling of the AP-1–MMP9–TGF-β pathway.

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Section: Discussionmentioning

confidence: 59%

Trypanosoma cruzi Induces the PARP1/AP-1 Pathway for Upregulation of Metalloproteinases and Transforming Growth Factor β in Macrophages: Role in Cardiac Fibroblast Differentiation and Fibrosis in Chagas Disease

Choudhuri

Garg

2020

mBio

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“…The most active targets include PARP1, and more recently PARP14 (Berger et al 2018;Qin et al 2019). Studies that used the small molecule inhibitors demonstrated that PARP suppression reduces proinflammatory responses or enhances anti-inflammatory functions of macrophages (Haskó et al 2002;Wang et al 2013;Shrestha et al 2016;Dharwal et al 2019). Recent work showed that PARP inhibition in combination with PD-1/PD-L1 blockade could be effective for BRCA1-deficient tumors by activating antigen presenting cells such as dendritic cells via the cGAS-STING pathway (Jiao et al 2017;Ding et al 2018;Dunphy et al 2018).…”

Section: Parps In Cancer Immunologymentioning

confidence: 99%

The impact of PARPs and ADP-ribosylation on inflammation and host–pathogen interactions

et al. 2020

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Poly-adenosine diphosphate-ribose polymerases (PARPs) promote ADP-ribosylation, a highly conserved, fundamental posttranslational modification (PTM). PARP catalytic domains transfer the ADP-ribose moiety from NAD+ to amino acid residues of target proteins, leading to mono- or poly-ADP-ribosylation (MARylation or PARylation). This PTM regulates various key biological and pathological processes. In this review, we focus on the roles of the PARP family members in inflammation and host–pathogen interactions. Here we give an overview the current understanding of the mechanisms by which PARPs promote or suppress proinflammatory activation of macrophages, and various roles PARPs play in virus infections. We also demonstrate how innovative technologies, such as proteomics and systems biology, help to advance this research field and describe unanswered questions.

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“…Accordingly, PARP enzymatic inhibition or PARP-1 gene knock causes the inhibition of cell migration to inflammatory sites [ 186 ]. Additionally, small molecule inhibitors acting on PARP reduced proinflammatory responses or enhanced anti-inflammatory functions of macrophages [ 187 , 188 ]. Nonetheless, it is involved in gene expression and the activation of neutrophils, macrophages, dendritic cells, microglia and other cell types [ 189 , 190 , 191 ].…”

Section: Targeting Ddr To Defeat Cancermentioning

confidence: 99%

DNA Damage Response and Immune Defense

Nastasi

Mannarino

D’Incalci

2020

IJMS

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DNA damage is the cause of numerous human pathologies including cancer, premature aging, and chronic inflammatory conditions. The DNA damage response (DDR), in turn, coordinates DNA damage checkpoint activation and promotes the removal of DNA lesions. In recent years, several studies have shown how the DDR and the immune system are tightly connected, revealing an important crosstalk between the two of them. This interesting interplay has opened up new perspectives in clinical studies for immunological diseases as well as for cancer treatment. In this review, we provide an overview, from cellular to molecular pathways, on how DDR and the immune system communicate and share the crucial commitment of maintaining the genomic fitness.

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PARP-1 inhibition provides protection against elastase-induced emphysema by mitigating the expression of matrix metalloproteinases

Cited by 18 publications

References 45 publications

Trypanosoma cruzi Induces the PARP1/AP-1 Pathway for Upregulation of Metalloproteinases and Transforming Growth Factor β in Macrophages: Role in Cardiac Fibroblast Differentiation and Fibrosis in Chagas Disease

Trypanosoma cruzi Induces the PARP1/AP-1 Pathway for Upregulation of Metalloproteinases and Transforming Growth Factor β in Macrophages: Role in Cardiac Fibroblast Differentiation and Fibrosis in Chagas Disease

The impact of PARPs and ADP-ribosylation on inflammation and host–pathogen interactions

DNA Damage Response and Immune Defense

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