Progranulin Plays a Central Role in Host Defense during Sepsis by Promoting Macrophage Recruitment

Song, Zigen; Zhang, Xuemei; Zhang, Liping; Xu, Fang; Tao, Xintong; Zhang, Hua; Lin, Xue; Kang, Lihua; Yu, Xiang; Lai, Xaiofei; Zhang, Qun; Huang, Kun; Dai, Yan; Yin, Yibing; Cao, Ju

doi:10.1164/rccm.201601-0056oc

Cited by 50 publications

(37 citation statements)

References 43 publications

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“…Interestingly, a reduction in PGRN expression has been observed in an acute kidney injury mouse model after ischemia/reperfusion and in the cerebrospinal fluid of patients with subarachnoid hemorrhage (Zhou, Tang, et al, ; Zhou, Xie, et al, ), suggesting that PGRN expression in inflammatory disorders may be, in part, dependent on the particular disease model. In pulmonary inflammatory diseases, PGRN overexpression is also apparent in the lung tissues of a mouse endotoxic shock model (Yu et al, ), in the sera of patients with sepsis (Song et al, ), and in the BALF from patients with community‐acquired pneumonia (Zou et al, ). However, the levels of PGRN in the BALF are decreased in mice on day three after induction with of ALI by intraperitoneal injection of LPS (Guo et al, ).…”

Section: Discussionmentioning

confidence: 99%

“…Previous studies have shown that PGRN plays a critical role in a series of physiologic and pathological processes, including wound healing, inflammation, and apoptosis (Cerezo et al, ; Ma, Matsuwaki, Yamanouchi, & Nishihara, ; Zhou, Tang, et al, ). PGRN‐deficient mice display severe lung injury and fatal inflammatory responses when the mice are subjected to sepsis or endotoxic shock (Song et al, ; Zhou, Tang, et al, ). Consistently, we have found that PGNR expression is significantly down‐regulated in the bronchial alveolar lavage fluid (BALF) of mice with ALI and that administration of recombinant murine PGRN significantly reduces LPS‐induced lung inflammation (Guo et al, ).…”

Section: Introductionmentioning

confidence: 99%

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miR‐34b‐5p inhibition attenuates lung inflammation and apoptosis in an LPS‐induced acute lung injury mouse model by targeting progranulin

Xie

Wang

et al. 2018

Journal Cellular Physiology

129

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Inflammation and apoptosis play important roles in the initiation and progression of acute lung injury (ALI). Our previous study has shown that progranulin (PGRN) exerts lung protective effects during LPS‐induced ALI. Here, we have investigated the potential roles of PGRN‐targeting microRNAs (miRNAs) in regulating inflammation and apoptosis in ALI and have highlighted the important role of PGRN. LPS‐induced lung injury and the protective roles of PGRN in ALI were first confirmed. The function of miR‐34b‐5p in ALI was determined by transfection of a miR‐34b‐5p mimic or inhibitor in intro and in vivo. The PGRN level gradually increased and subsequently significantly decreased, reaching its lowest value by 24 hr; PGRN was still elevated compared to the control. The change was accompanied by a release of inflammatory mediators and accumulation of inflammatory cells in the lungs. Using bioinformatics analysis and RT‐PCR, we demonstrated that, among 12 putative miRNAs, the kinetics of the miR‐34b‐5p levels were closely associated with PGRN expression in the lung homogenates. The gain‐ and loss‐of‐function analysis, dual‐luciferase reporter assays, and rescue experiments confirmed that PGRN was the functional target of miR‐34b‐5p. Intravenous injection of miR‐34b‐5p antagomir in vivo significantly inhibited miR‐34b‐5p up‐regulation, reduced inflammatory cytokine release, decreased alveolar epithelial cell apoptosis, attenuated lung inflammation, and improved survival by targeting PGRN during ALI. miR‐34b‐5p knockdown attenuates lung inflammation and apoptosis in an LPS‐induced ALI mouse model by targeting PGRN. This study shows that miR‐34b‐5p and PGRN may be potential targets for ALI treatments.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

miR‐34b‐5p inhibition attenuates lung inflammation and apoptosis in an LPS‐induced acute lung injury mouse model by targeting progranulin

Xie

Wang

et al. 2018

Journal Cellular Physiology

129

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“…Administration of recombinant PGRN alleviated the symptoms of inflammatory arthritis in TNF transgenic mouse and other RA animal models (18). Although PGRN has been reported to regulate the recruitment of macrophages via impacting the expression of CCL2 (62), one anti-inflammatory mechanism of PGRN that is often overlooked is its regulatory role in IL-10 production.…”

Section: Discussionmentioning

confidence: 99%

Progranulin Controls Sepsis via C/EBPα-Regulated Il10 Transcription and Ubiquitin Ligase/Proteasome-Mediated Protein Degradation

Yan

Ding

Kim

et al. 2016

The Journal of Immunology

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Progranulin (PGRN) is a widely expressed, pleiotropic protein that is involved in diverse biological processes including cellular proliferation, neuron development and wound healing. However, the role of PGRN in the regulation of pathogen-induced systemic inflammation and the mechanisms involved have not been established. Here we show that PGRN-deficient mice display heightened mortality in models of polymicrobial sepsis and endotoxinemia, with increased tissue levels of inflammatory cytokines and reduced IL-10 production. Conversely, administration of recombinant PGRN decreases the susceptibility of PGRN-deficient mice to LPS-induced endotoxemic shock and augments IL-10 production by LPS-activated macrophages in a TNFR-dependent manner. Molecular analysis reveals a direct role of the transcription factor CCAAT/enhancer-binding protein alpha (C/EBPα) in PGRN-regulated IL-10 expression. C/EBPα–deficient macrophages produce less IL-10 in response to LPS. Further, mice deficient in C/EBPα in hematopoietic cells are highly vulnerable to LPS-induced septic shock. Lastly, the defective IL-10 production by PGRN-deficient cells is primarily due to reduced C/EBPα protein stability via the E3 ubiquitin conjugating enzyme E6AP and proteasome-mediated degradation. This study provides the first evidence that PGRN is a non-redundant regulator of systemic inflammation via modulating the levels and activity of C/EBPα, IL-10 and the ubiquitin-proteasome proteolysis pathway. The results bear strong and profound implications for PGRN-insufficiency and its mutation-associated systemic and organ-specific inflammatory human diseases.

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“…Based on the fact that PGRN functions as an antimicrobial factor [19,20,24], it may lead to the hypothesis that PGRN represents a new target for immunotherapy against chronic HBV infection.…”

Section: Discussionmentioning

confidence: 99%

Serum progranulin levels are elevated in patients with chronic hepatitis B virus infection, reflecting viral load

et al. 2016

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Progranulin Plays a Central Role in Host Defense during Sepsis by Promoting Macrophage Recruitment

Abstract: This proof-of-concept study supports a central role of progranulin-dependent macrophage recruitment in host defense to sepsis, opening new opportunities to host-directed therapeutic strategy that manipulate host immune response in the treatment of sepsis.

Cited by 50 publications

References 43 publications

miR‐34b‐5p inhibition attenuates lung inflammation and apoptosis in an LPS‐induced acute lung injury mouse model by targeting progranulin

miR‐34b‐5p inhibition attenuates lung inflammation and apoptosis in an LPS‐induced acute lung injury mouse model by targeting progranulin

Progranulin Controls Sepsis via C/EBPα-Regulated Il10 Transcription and Ubiquitin Ligase/Proteasome-Mediated Protein Degradation

Serum progranulin levels are elevated in patients with chronic hepatitis B virus infection, reflecting viral load

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