Progranulin inhibits LPS-induced macrophage M1 polarization via NF-кB and MAPK pathways

Liu, Lianlian; Guo, Hongmei; Song, Aimei; Huang, Jian; Zhang, Yu; Jin, Shanshan; Li, Shutong; Zhang, Liguo; Yang, Chengzhe; Yang, Pishan

doi:10.1186/s12865-020-00355-y

Cited by 160 publications

(88 citation statements)

References 46 publications

(61 reference statements)

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“… 43 HMGB1-RAGE axis has also been proved to induce autophagy under diverse disorders. 44 , 45 So we speculated that PGRN may render protective ability through inhibiting HMGB1-RAGE and downstream MAPKs signaling during HDM-induced asthma, which was partly in accordance with a previous study by Liu et al 46 There were some limitations that we only evaluated the changes of RAGE expression in PGRN-treated mice lungs under HDM exposure. The correlation between PGRN and other HMGB1-mediated signaling pathways is warranted to be elucidated in further study.…”

Section: Discussionsupporting

confidence: 84%

Progranulin Protects Against Airway Remodeling Through the Modulation of Autophagy via HMGB1 Suppression in House Dust Mite-Induced Chronic Asthma

Liu¹,

Shan²,

Zhang³

et al. 2021

JIR

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Purpose Airway remodeling is an important feature of chronic asthma, and yet there are few effective therapeutic strategies. Progranulin (PGRN) has been shown to have lung protective functions, but the role of PGRN in asthmatic airway remodeling is unclear. We aim to explore the protective potential of PGRN on house dust mite (HDM)-induced airway remodeling and the underlying mechanisms. Methods In this study, a murine model of chronic asthma was established by HDM sensitization and challenge. Recombinant PGRN was intranasally administrated to mice during the phase of HDM challenge. TGF-β1-treated human airway epithelial BEAS-2B cells were utilized to explore the effect of PGRN on airway epithelia exposed to profibrotic conditions and molecular mechanisms. Results We found that PGRN treatment attenuated HDM-induced airway remodeling, as evidenced by the suppression of collagen accumulation, mucus overproduction and airway smooth muscle synthesis in HDM-challenged asthmatic mice lungs. Meanwhile, PGRN also reversed the increased levels of autophagy markers and autophagosomes in airway epithelia under mimic asthmatic conditions, thereby controlling the fibrotic process in vivo and in vitro. Specifically, overexpressed HMGB1 and the subsequent RAGE/MAPKs signaling activation due to HDM exposure were abrogated in PGRN-treated asthmatic mice. Furthermore, knockdown of HMGB1 expression significantly restrained the fibrosis formation in TGF-β1-induced airway epithelia accompanied by the downregulation of autophagic activity. However, enhancement of extracellular HMGB1 levels blunted the inhibition of autophagic flux by PGRN in airway epithelia, thereby resulting in the augmentation of collagen synthesis and fibrosis. Conclusion Taken together, our data revealed that PGRN protected against asthmatic airway remodeling by negatively regulating autophagy via HMGB1 suppression, which might provide new insights into the therapeutic options for HDM-induced chronic asthma.

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Section: Discussionsupporting

confidence: 84%

Progranulin Protects Against Airway Remodeling Through the Modulation of Autophagy via HMGB1 Suppression in House Dust Mite-Induced Chronic Asthma

Liu¹,

Shan²,

Zhang³

et al. 2021

JIR

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“…The released IL-1β and IL-18 can then recruit more macrophages to phagocytose cell debris and kill pathogens by enhancing phagosome acidification, thereby amplifying inflammatory responses and bone resorption ( 99 ). In addition to these bone-resident macrophages that may first sense most danger-related stimuli in the local environment, macrophages derived from circulating mononuclear cells may also be recruited to infected bone tissue ( 128 ). These macrophages may be activated into pro-inflammatory M1-like macrophages or anti-inflammatory M2-like macrophages, both of which are characterized by cytokine secretion patterns and functional capabilities.…”

Section: Mechanisms Of Bone Loss Related To Inflammasomesmentioning

confidence: 99%

Inflammasomes in Alveolar Bone Loss

Ling

Jiang

2021

Front. Immunol.

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Bone remodeling is tightly controlled by osteoclast-mediated bone resorption and osteoblast-mediated bone formation. Fine tuning of the osteoclast–osteoblast balance results in strict synchronization of bone resorption and formation, which maintains structural integrity and bone tissue homeostasis; in contrast, dysregulated bone remodeling may cause pathological osteolysis, in which inflammation plays a vital role in promoting bone destruction. The alveolar bone presents high turnover rate, complex associations with the tooth and periodontium, and susceptibility to oral pathogenic insults and mechanical stress, which enhance its complexity in host defense and bone remodeling. Alveolar bone loss is also involved in systemic bone destruction and is affected by medication or systemic pathological factors. Therefore, it is essential to investigate the osteoimmunological mechanisms involved in the dysregulation of alveolar bone remodeling. The inflammasome is a supramolecular protein complex assembled in response to pattern recognition receptors and damage-associated molecular patterns, leading to the maturation and secretion of pro-inflammatory cytokines and activation of inflammatory responses. Pyroptosis downstream of inflammasome activation also facilitates the clearance of intracellular pathogens and irritants. However, inadequate or excessive activity of the inflammasome may allow for persistent infection and infection spreading or uncontrolled destruction of the alveolar bone, as commonly observed in periodontitis, periapical periodontitis, peri-implantitis, orthodontic tooth movement, medication-related osteonecrosis of the jaw, nonsterile or sterile osteomyelitis of the jaw, and osteoporosis. In this review, we present a framework for understanding the role and mechanism of canonical and noncanonical inflammasomes in the pathogenesis and development of etiologically diverse diseases associated with alveolar bone loss. Inappropriate inflammasome activation may drive alveolar osteolysis by regulating cellular players, including osteoclasts, osteoblasts, osteocytes, periodontal ligament cells, macrophages, monocytes, neutrophils, and adaptive immune cells, such as T helper 17 cells, causing increased osteoclast activity, decreased osteoblast activity, and enhanced periodontium inflammation by creating a pro-inflammatory milieu in a context- and cell type-dependent manner. We also discuss promising therapeutic strategies targeting inappropriate inflammasome activity in the treatment of alveolar bone loss. Novel strategies for inhibiting inflammasome signaling may facilitate the development of versatile drugs that carefully balance the beneficial contributions of inflammasomes to host defense.

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“…6,7 LPS-induced inflammation is the leading cause of multiple organ failure in sepsis. LPS binds to the TLR4 macrophage membrane receptor, to trigger the differentiation of M1 phenotype macrophages involved in pro-inflammatory responses and the production of pro-inflammatory related factors through the activation of intracellular signaling cascades, including the mitogen-activated protein kinase (MAPK), 8 nuclear factor kappa-B (NF-κB), 6,8 Janus kinase (JAK)-signal transducer and activator of transcription (STAT) pathways. 9 Activated macrophages are usually divided into two categories, M1-like and M2-like macrophages.…”

Section: Introductionmentioning

confidence: 99%

The ACE2-Ang-(1‑7)-Mas Axis Modulates M1/M2 Macrophage Polarization to Relieve CLP-Induced Inflammation via TLR4-Mediated NF-кb and MAPK Pathways

Pan¹,

Huang²,

Wang³

et al. 2021

JIR

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has been identified as an important anti-inflammatory and anti-fibrotic factor. This study determined how the ACE2-Ang-(1-7)-Mas axis affected M1/ M2 macrophage polarization and thus contributed to anti-inflammatory processes in the cecal ligation and puncture (CLP)-induced inflammation model. Materials and Methods: ELISA, western blotting, and qRT-PCR were used to verify that Ang-(1-7) decreased the expression of pro-inflammatory cytokines and increased anti-inflammatory cytokines. The differentiation of M1/M2 macrophages was assessed by flow cytometry for assessing the cell-surface markers, CD86 and CD206. The related key receptors and pathways were analyzed by Western blotting, qRT-PCR, and immunofluorescence. CLP-induced inflammatory mice models were used for in vivo studies. Hematoxylin and eosin and immunohistochemical and immunofluorescence staining protocols were used to analyze histological changes in the spleen, and the related key pathway proteins were analyzed by western blotting. Results: Ang-(1-7) decreased the expressions of the TNF-α and IL-6 pro-inflammatory cytokines and increased the expressions of the IL-4 and IL-10 anti-inflammatory cytokines. INOS and TNFα, which represented M1 macrophage polarization, were decreased by Ang-(1-7). ARG1 and CD163, which represented M2 macrophage polarization, were increased by Ang-(1-7). Both Mas receptor and ACE2 are expressed on macrophages. Furthermore, the ACE2-Ang-(1-7)-MAS axis modulated macrophage polarization by ameliorating TLR4 expression and regulating the NF-кB and MAPK pathways. In addition, splenomegaly and macrophage infiltration were observed in the spleen of the CLP-induced mouse models and macrophages in the spleen suspension of CLP models were shifted to M1 phenotype and were effectively inhibited by Ang-(1-7) via the TLR4mediated NF-кB and MAPK pathways, which could be partially rescued by A-779. Ang-(1-7) inhibited inflammatory responses in vivo and in vitro, and repressed macrophage polarization toward the M1 phenotype and promoted it toward the M2 phenotype, which provided new evidence for the anti-inflammation activity of the ACE2-Ang -(1-7)-MAS axis. Conclusion:

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Progranulin inhibits LPS-induced macrophage M1 polarization via NF-кB and MAPK pathways

Cited by 160 publications

References 46 publications

Progranulin Protects Against Airway Remodeling Through the Modulation of Autophagy via HMGB1 Suppression in House Dust Mite-Induced Chronic Asthma

Progranulin Protects Against Airway Remodeling Through the Modulation of Autophagy via HMGB1 Suppression in House Dust Mite-Induced Chronic Asthma

Inflammasomes in Alveolar Bone Loss

The ACE2-Ang-(1‑7)-Mas Axis Modulates M1/M2 Macrophage Polarization to Relieve CLP-Induced Inflammation via TLR4-Mediated NF-кb and MAPK Pathways

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