CCL2 and T cells in pulmonary fibrosis: an old player gets a new role

Osafo-Addo, Awo; Herzog, Erica L.

doi:10.1136/thoraxjnl-2017-210517

Cited by 15 publications

(11 citation statements)

References 20 publications

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“…Recent studies showed that the CCL2/CCR2 axis has a vital role in the fibrotic formation in some diseases, including pulmonary fibrosis, renal fibrosis, and non-alcoholic liver fibrosis. In addition, it also regulates chemotactic macrophage infiltration (27,47,48). Wang et al speculated that the CCL2/CCR2 axis is closely related to the aggregation of myeloidderived inhibitory cells (MDSCs) and T cell function inhibition in pulmonary fibrosis and lung cancer (49).…”

Section: Discussionmentioning

confidence: 99%

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Activated Hepatic Stellate Cells Induce Infiltration and Formation of CD163+ Macrophages via CCL2/CCR2 Pathway

Shi

Zheng

et al. 2021

Front. Med.

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Background: Activated hepatic stellate cells (aHSCs) regulate the function of immune cells during liver fibrosis. As major innate cells in the liver, macrophages have inducible plasticity. Nevertheless, the mechanisms through which aHSCs regulate macrophages' phenotype and function during liver fibrosis and cirrhosis remain unclear. In this study, we examined the immunoregulatory function of aHSCs during liver fibrosis and explored their role in regulating macrophage phenotype and function.Methods: A total of 96 patients with different stages of chronic hepatitis B-related liver fibrosis were recruited in the study. Metavir score system was used to evaluate the degree of fibrosis. The expression of hepatic CCL2 and M2 phenotype macrophage marker CD163 were detected by immunohistochemistry, and the relationship among hepatic CD163, CCL2, and fibrosis scores were also explored. In the in vitro model, the aHSCs isolated from human liver tissues and THP-1-derived M0-type macrophages (M0MΦ) were co-cultured to observe whether and how aHSCs regulate the phenotype and function of macrophages. To explore whether CCL2/CCR2 axis has a crucial role in macrophage phenotypic changes during liver fibrosis, we treated the M0MΦ with recombinant human CCL2 or its specific receptor antagonist INCB-3284. Furthermore, we used LX2 and TGF-β-activated LX2 to mimic the different activation statuses of aHSCs to further confirm our results.Results: In patients, the infiltration of M2 macrophages increased during the progression of liver fibrosis. Intriguingly, as a key molecule for aHSC chemotactic macrophage aggregation, CCL2 markedly up-regulated the expression of CD163 and CD206 on the macrophages, which was further confirmed by adding the CCR2 antagonist (INCB 3284) into the cell culture system. In addition, the TGF-β stimulated LX2 further confirmed that aHSCs up-regulate the expression of CD163 and CD206 on macrophages. LX2 stimulated with TGF-β could produce more CCL2 and up-regulate other M2 phenotype macrophage-specific markers, including IL-10, ARG-1, and CCR2 besides CD163 and CD206 at the gene level, indicating that the different activation status of aHSCs might affect the final phenotype and function of macrophages.Conclusions: The expression of the M2 macrophage marker increases during liver fibrosis progression and is associated with fibrosis severity. AHSCs can recruit macrophages through the CCL2/CCR2 pathway and induce M2 phenotypic transformation.

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Section: Discussionmentioning

confidence: 99%

“…CCL2, also known as monocyte chemotactic factor 1 (MCP1), regulates the migration and infiltration of monocytes/macrophages through combination with its specific receptor CCR2 (26,27). It has been reported that CCL2/CCR2 axis has a vital role during fibrosis (28)(29)(30)(31).…”

Section: Introductionmentioning

confidence: 99%

Activated Hepatic Stellate Cells Induce Infiltration and Formation of CD163+ Macrophages via CCL2/CCR2 Pathway

Shi

Zheng

et al. 2021

Front. Med.

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“…Recent studies showed that the CCL2/CCR2 axis plays a vital role in the brotic formation in some diseases, including pulmonary brosis, renal brosis and nonalcoholic liver brosis, in addition to chemotactic macrophage in ltration [27,44,45]. It is found that CCL2/CCR2 axis was closely related to aggregation of myeloid-derived inhibitory cells (MDSCs) and inhibition of T cell function in pulmonary brosis and lung cancer [46].…”

Section: Disscussionmentioning

confidence: 99%

“…CCL2, also known as monocyte chemotactic factor 1 (MCP1), mainly regulates migration and in ltration of monocytes/macrophages through combination with its speci c receptor CCR2 [26,27]. It has reported that CCL2/CCR2 axis plays a vital role during brosis [28][29][30].…”

Section: Introductionmentioning

confidence: 99%

Activated Hepatic Stellate Cells Induce Infiltration and Formation of CD163+ Macrophages via CCL2/CCR2 Pathway

Shi

Zheng

Jiang

et al. 2020

Preprint

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Background: Growing evidence indicates that activated hepatic stellate cells (aHSCs) play unexpected roles in regulating immune cells’ function during liver fibrosis. Macrophages feature with inducible plasticity according to the circumstances while patrol for potential pathogens. However, studies seldom investigate whether and how the aHSCs regulate the phenotype and function of macrophages during liver fibrosis. Methods: 96 patients with different stages of liver fibrosis were involved in our study. Metavir score system was used to evaluate the degree of fibrosis. The expression of hepatic CCL2 and CD163 were detected by immunohistochemistry, and the relationship among CD163, CCL2, and fibrosis scores were explored. We co-cultured the aHSCs and THP-1-derived M0-type macrophages (M0MФ) to observe whether aHSCs modulate the expression of CD163 on macrophages in vitro. Furthermore, we treated the M0MФ with aHSCs’ supernatant and investigated the production of CCL2 in aHSCs by ELISA and immunofluorescence assay. To explore whether CCL2/CCR2 axis plays a crucial role in macrophage phenotypic changes during liver fibrosis, we used recombinant CCL2 and its specific receptor antagonist. Moreover, we employed LX2 system to confirm our results. Results: We found that hepatic M2 macrophages (CD163+) infiltration increased in different stages of liver fibrosis (F0-1: 34.95±18.12; F2-3: 77.57±32.48; F4: 99.62±40.84, F0-1 vs. F2-3, P<0.001; F2-3 vs. F4, P=0.074). After in vitro co-cultured with aHSCs, the macrophages expressed higher levels of CD163 (29.5±6.1% vs. 2.7±1.1%) as well as CD206 (28.0±4.2% vs. 2.4±1.2%) compared with the control. Then we found aHSC supernatant up-regulated the expression of CD163 (26.1±2.8%) and CD206 (25.8±3.8%) on macrophages independently. We noted aHSCs’ supernatant contained a high level of CCL2, which increased dramatically while TGF-β stimulation. Meanwhile, CCL2 staining score increased with the progress of fibrosis ( N: 23.26±13.85; F1: 4 8.56±19.18; F2: 58.25±16.24; F3: 81.32±18.48; F4: 110.93±24.75). Intriguingly, CCL2 significantly up-regulated the expression of CD163 (27.6±7.0%) and CD206 (26.5±5.1%) on macrophages besides inducing their aggregation. Results were confirmed with LX2 co-culture system. Conclusions: (1) The expression of M2 macrophage marker CD163 increased significantly during the progress of liver fibrosis and associated with fibrosis severity. (2) AHSCs can recruit macrophages and induce their M2 phenotypic transformation through CCL2/CCR2 pathway.

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“…S3F ). The mRNA expression level of chemokines that mediating neutrophil infiltration (such as Cxcl1 , Cxcl5 , and Csf3 [ 47 , 48 ]) increased in hyperglycemic ICH mice compared with that in normoglycemic ICH mice, but not the chemokines mediating monocyte/macrophage infiltration (such as Il2 and CSF2 [ 49 , 50 ]) or T cell infiltration (such as Ccl2 and Ccl3 [ 51 , 52 ]) ( Figs. S3F and G ).…”

Section: Resultsmentioning

confidence: 99%

Reduction of lactoferrin aggravates neuronal ferroptosis after intracerebral hemorrhagic stroke in hyperglycemic mice

et al. 2022

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Diabetic hyperglycemia aggravates the prognosis of intracerebral hemorrhagic stroke (ICH) in the clinic. In addition to hematoma expansion and increased inflammation, how diabetic hyperglycemia affects the outcomes of ICH is still unclear. We found that streptozotocin-induced diabetic hyperglycemia not only increased neutrophil infiltration, but also changed the gene expression profile of neutrophils, including lactoferrin (Ltf) encoding gene Ltf . Peroxisome proliferator-activated receptor γ (PPARγ) transcribed Ltf and the lack of neutrophilic Ltf transcription and secretion exacerbated neuronal ferroptosis by accumulating intraneuronal iron. Furthermore, the administration of recombinant Ltf protected against neuronal ferroptosis and improved neurobehavior in hyperglycemic ICH mice, and vice versa . These results indicate that supplementing Ltf or inhibiting neuronal ferroptosis are promising potential strategies to improve the acute outcomes of diabetic ICH in the clinic.

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CCL2 and T cells in pulmonary fibrosis: an old player gets a new role

Cited by 15 publications

References 20 publications

Activated Hepatic Stellate Cells Induce Infiltration and Formation of CD163+ Macrophages via CCL2/CCR2 Pathway

Activated Hepatic Stellate Cells Induce Infiltration and Formation of CD163+ Macrophages via CCL2/CCR2 Pathway

Activated Hepatic Stellate Cells Induce Infiltration and Formation of CD163+ Macrophages via CCL2/CCR2 Pathway

Reduction of lactoferrin aggravates neuronal ferroptosis after intracerebral hemorrhagic stroke in hyperglycemic mice

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