Anti-inflammatory effects of Irisin in LPS-stimulated RAW264.7 macrophages by inhibiting the MAPK pathway

doi:10.21203/rs.3.rs-1658198/v1

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Anti-inflammatory effects of Irisin in LPS-stimulated RAW264.7 macrophages by inhibiting the MAPK pathway

https://doi.org/10.21203/rs.3.rs-1658198/v1

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Aims Irisin is a newly discovered actin that has been shown to be effective against inflammation-related symptoms. The aim of this study was to investigate the influence of Irisin on LPS-induced inflammation in vitro and to investigate the role of the mitogen-activated protein kinase (MAPK) pathway in the protecting effect of Irisin in LPS-stimulated RAW 264.7 macrophages.

Methods Cell viability was assessed using MTT assay and flow cytometry, cell morphology was measured by optical microscope, IL-12 and IL-23 were detected by Elisa, and the levels of related proteins were analyzed by western blot. Phagocytosis of zymosan and clearance of apoptotic cells were measured.

Results MTT assay and flow cytometry results showed that LPS-induced cytotoxicity was reversed by Irisin(p<0.001), after coincubation with Irisin, the level of IL-12 and IL-23 decreased in LPS-stimulated RAW264.7 macrophages(p>0.05). Irisin pretreatment significantly inhibited the phosphorylation of ERK and AKT and increased the expression of PPAR α and PPAR γ(p<0.05). LPS-induced enhancement of phagocytosis(p<0.05) and cell clearance was reversed by Irisin pretreatment(p<0.001).

Conclusions Irisin ameliorated LPS-induced inflammation by inhibiting cytotoxicity and apoptosis, and this protective effect may be mediated through the MAPK pathway.

Irisin

LPS

RAW264

PPAR

ERK

AKT

MAPK

Irisin is cleaved and secreted from the fibronectin type III domain containing 5 (FNDC5) and exerts protective effects against metabolic diseases in humans and mice, and its production is stimulated by exercise and exposure to cold [1, 2]. Irisin is known to protect against metabolic disturbances and stimulates adipocyte transition from white to brown through the MAP kinase and ERK MAP kinase signaling [3, 4]. There have been a large number of clinical and experimental research reports that Irisin is a key factor in the process of pathogenic diseases [5–8]. Recent studies have found that Irisin plays an important biological function in other system diseases, such as regulating depression [9], regulates osteoblast proliferation[10], and cortical bone mass[11]. Irisin can also replace ischemic neuronal damage by activating Akt and ERK1/2 signaling pathways [12].

Physical activity has been shown to have anti-inflammatory effects [13]. It has been reported that exercise is proposed as an auxiliary anti-inflammatory treatment, physiological movement and inflammatory markers are negatively related [14, 15]. Systemic chronic inflammation is diminished by regular exercise in both longitudinal and cross-sectional studies [16]. A recent study shows that voluntary exercise can attenuate the severity of colonic damage in mice fed with a High-Fat Diet through the release of protective Irisin [17]. Liu et al found that voluntary exercise may prevent ulcerative colitis [18], which illustrates the anti-inflammatory effects of exercise.

Exercise and FNDC5/irisin have been shown to play a protective role in neuroinflammation [19], obese inflammation in mouse [20], and cardiac hypertrophy [21]. FNDC4 has been shown to be an anti-inflammatory factor in macrophages and ameliorates induced colitis in a mouse model. FNDC5 is a precursor for Irisin synthesis sharing high homology with FNDC4[22]. Therefore, we speculate that Irisin may play an important role in the treatment of UC.

In our previous in vivo experiments, Irisin has been shown to improve inflammation in a mouse model of UC [23], however, there are no in vitro studies on the association between Irisin and inflammation. Therefore, the purpose of this study was to investigate the effect of Irisin on inflammation by observing LPS-induced RAW264.7 in vitro.

Macrophage cell culture

RAW264.7 macrophage were cultured in Dulbecco’s Modified Eagle’s Medium (DMEM; Corning, USA) containing 10% fetal bovine serum (FBS; Corning, USA) and 1% penicillin/streptomycin (Invitrogen, USA), in 37°C, 5% CO²incubator.

Cell MTT test

Cell viability was tested by MTT assay, 1 x 10⁵cells were seeded in a 96-well plate. After incubation for 24h, treated with various concentrations of LPS (Sigma, USA) (100, 500, 1000, 2000ng/ml) and Irisin(400ng/ml) (Phoenix Pharmaceuticals, Inc) for 24h. Then, 20 μl of 5% MTT (Solarbio, USA) solution was added to each well and incubated for 4 h. The supernatant was discarded and the resulting crystals were dissolved in DMSO (Solarbio, USA). Subsequently, the cells were further incubated (37 °C, 5% Co₂) for 10 min. Absorbance was measured at 490nm.

Cell morphology

RAW264.7 was cultured in 12-well plates at 1 × 10⁵ cells/well. After incubation for 24h, cells were cultured with medium, Irisin(400ng/ml), and LPS (1000ng/ml), respectively, or cells were pretreated with Irisin for 12 hours, and then LPS was added. Cell morphology was evaluated with light microscopy.

IL-12 and IL-23 levels

The levels of IL-12 and IL-23 in the supernatants of the four groups of cells were taken and detected by enzyme-linked immunosorbent assay (ELISA) kits (Hermes Criterion Biotechnology, Canada), respectively.

Macrophage phagocytosis test

The cell suspension concentration of log-phase RAW264.7 was adjusted to about 1 × 10⁵/mL and added 500 μL into each well of the 24-well plate in a 5% CO₂incubator for 24h at 37℃. Zymosan particles(Invitrogen, USA) were added to the cells. Phagocytosis was allowed to proceed for 30min. Cells were fixed with 4% paraformaldehyde for 30min at 4℃, then washed with PBS. The plate was examined by light microscopy at 400magnification using a Nikon Eclipse Ti2-E microscope (Nikon, Tokyo, Japan). Phagocytosis was determined by counting a total of 100 macrophages in at least four different fields in 400 magnification photomicrographs. Phagocytosis was assessed as the percentage of phagocytic cells (PP), mean of particles per cell (MNP), and as the phagocytic index (PI) determined as PI =PP x MNP.

Western Blot

The total proteins in each group were extracted with RIPA (Solarbio, USA), PMSF (Solarbio, USA), Protein Phosphatase Inhibitor (Solarbio, USA). The total protein was quantified by the BCA protein assay kit (Beyotime, China), and the protein was denatured at 95℃ for 5min. After electrophoresis, proteins were transferred on to polyvinylidene difluoride (PVDF) (Immobilon, Germany), followed by 5% non-fat milk（Solarbio, USA）to block the band. The band was then incubated with primary antibody (β-actin, Proteintech, China, Mouse, 1:5000, ERK1/2, Proteintech, China, Rabbit, 1:1000; Phospho-ERK1/2, Proteintech, China, Rabbit, 1:1000; AKT, Proteintech, China, Mouse, 1:2000; Phospho-AKT, Proteintech, China, Rabbit, 1:5000; PPAR α，Proteintech, China, Mouse, 1:1000; PPAR γ，Proteintech, China, Rabbit, 1:1000) at 4°C overnight, the appropriate secondary antibody HRP-conjugated affinity purified goat anti-rabbit, or goat anti-mouse lgG was applied at 1:5000 dilution and incubated for 1 hours at room temperature. Images were taken with Bio-Rad imaging system (Bio-Rad, USA) and analyzed by image analysis system for the optical density of the protein bands.

Flow Cytometry

To compare the apoptosis rate, RAW264.7 macrophages were divided into four groups, treated with a culture medium, Irisin (400 ng/ml), LPS (1000 ng/ml) alone, pretreated with Irisin, and then added with LPS. In addition, to assess the apoptotic rate of thymocytes, thymocytes and supernatants were collected after thymocytes were treated with dexamethasone (5 μM) (Yeasen, China) for 12 hours. then, centrifuged at 3000 r/min for 5 minutes, and resuspended in 500 μL Binding Buffer. Annexin V-FITC and PI (Procell, China) were added with 5 μL respectively, and flow cytometry quantitative detection was performed with FACS.

Apoptotic Cell Clearance Assay

Macrophages were seeded in 24-well plates. Apoptotic thymocytes were added to each well at a macrophage: thymocyte ratio of (1:10). Thymocytes were labeled with fluorescent cell tracking reagent (Invirtrogen, USA) before co-culture with macrophages. Phagocytosis assays were performed at 37°C for 1 hour. Macrophages were then washed thoroughly to remove non-phagocytic cells. Fix cells with 4% paraformaldehyde. Image analysis was performed by a fluorescence microscope (thymocytes, red). Quantify thymocytes phagocytosed by each macrophage using Image J by counting 50-100 macrophages in each well. Data are presented as phagocytosis index (PI). This index was defined as the total number of apoptotic cells phagocytosed by each macrophage present in the field of view.

Statistical analysis

Results were expressed as mean ± S.E.M, all data were analyzed by one-way ANOVA using Prism 9.0 software (GraphPad Software). P-values <0.05 were considered statistically significant.

Irisin Protected LPS-Induced Cell Injury

We first plated RAW264.7 macrophages into 96-well plates, and added different concentrations of LPS (0, 100, 500, 1000, 2000ng/mL), and used MTT assay to measure cell viability after 24 hours. Compared with the control group, LPS decreased cell viability in a dose-dependent manner. LPS significantly increased the percentage of apoptotic macrophages at a dose of 1000ng/ml (p<0.001) (Figure 1A), but Irisin pretreatment in concentration of 400ng/ml markedly reversed these effects. (p<0.001) (Figure 1B). This observation has been confirmed in the flow cytometry results and allowed us to assess overall cell viability (Figure 2).

Irisin changes the morphology of macrophages

To study the impact of Irisin on the cell morphology of RAW264.7 macrophages, we observed the alteration of cell morphology under an optical microscope after treated with medium, Irisin, LPS respectively. After 24h culture, the cell morphology changed significantly. The original shape of RAW264.7 was round. After LPS treatment, the cells were severely differentiated, and Irisin pretreatment could improve the cell shape (Figure 3).

Irisin Inhibited LPS-Induced change of protein

As shown in Figure 3, Irisin or LPS alone didn’t change the expression of ERK, AKT. Irisin pretreatment significantly reduced the phosphorylation of ERK and AKT as compared with LPS group, respectively (p<0.05). Consistently, LPS-induced decreases in PPARα and PPAR γ were significantly inhibited after irisin pretreatment. (p<0.05) (Figure 4).

Irisin decreased IL-12 and IL-23 levels induced by LPS

We found that Irisin can significantly decrease the elevated level of inflammatory factors in each group caused by LPS (p>0.05) (Figure 5). There was no significant difference in IL‑12 and IL‑23 levels between the control (11.20±42.05 and 553.6±27.42 pg/ml) and irisin (114.4±72.43 and 877.7±254.7 pg/ml, respectively) groups. However, the levels of IL-12 (224.7±168) and IL-23 (1121±455.6 pg/ml) were significantly increased in the LPS group compared with the control group. Irisin significantly reduced LPS-mediated upregulation of IL-12 (123.4±73.43 pg/ml) and IL-23(955.1±379.8 pg/ml), but the decrease was not significant.

LPS enhances zymosan phagocytosis

Phagocytosis is a basic immune response reflecting the immune status of the body[24]. Compared with the control group, the Irisin-alone culture was unchanged, and its PI was 3.22±0.33. LPS treatment increased phagocytosis efficiency, with PI increasing from 2.68±0.09 in cells cultured in medium only to 5.07±0.18 in cells cultured with LPS 1000ng/ml (p<0.05) (Figure 6). After LPS treatment, the uptake of the zymosan in macrophages was gradually increased, while after irisin pretreatment, its PI was 4.43±0.32 (p<0.01), which greatly reduced this effect.

LPS enhances cell clearance

Over 90% cells become phosphatidylserine positive after incubation with 5μM dexamethasone. (Figure 7A) The fluorescent-labeled apoptotic cells were engulfed by macrophage. Cells cultured in medium or irisin alone had little effect on apoptotic thymocyte ingestion (PI 0.33 ± 0.02 and PI 0.37 ± 0.14, respectively), whereas LPS significantly enhanced apoptotic thymocyte ingestion (PI 2.58 ± 0.42) (p<0.0001), Irisin pretreatment alleviated ingestion (PI 1.87±0.32) (p<0.001).

Irisin is reported to ameliorate metabolic diseases such as diabetes and obesity, insulin resistance [25–27], moreover, Irisin has a role in nervous system disease, including neuronal injury [12], Alzheimer's disease[28], besides, Irisin has anti-inflammatory properties in bone turnover changes[29], obese[20], gut[30]. The anti-inflammatory effects of exercise may be attributed to the release of Irisin [2]. The FNDC4 is highly homologous to FNDC5/Irisin, and has been shown to be an anti-inflammatory factor in macrophages and ameliorate colitis in mice[22]. However, the effect of irisin on LPS-induced inflammation in vitro has not been investigated. Therefore, it is of great significance to study the anti-inflammatory mechanism of irisin.

The agonist of PPAR γ plays an anti-inflammatory role in human brain disease [31] and atherosclerosis[32] by regulating pro-inflammatory cytokine expression [33–35]. Due to its anti-inflammatory and anti-fibrotic properties, PPAR γ has been reported to be a target of IBD [36]. PPAR γ ameliorates HFD-induced obese mice by voluntary exercise due to inhibition of inflammatory cytokines [37]. Activation of PPAR γ has been demonstrated to inhibit colonic inflammation in ulcerative colitis (UC) or animal models of UC [38], which is mediated by the production of intestinal glucocorticoid [18]. The PPAR α signaling in the anti-inflammatory activity of glucocorticoids modulated and improved the anti-inflammatory response in IBD murine [39]. There was a positive effect of rSj16 on DSS-induced colitis by diminishing pro-inflammatory cytokine production and upregulating immunoregulatory cytokine production[40], which was mediated by PPARα pathway inhibition. Studies have revealed that PPAR is increased at the mRNA level by Irisin treatment [1]. This is consistent with our results that Irisin pretreatment reversed the decreased expression of PPARα and PPAR γ caused by LPS, indicating that Irisin has a therapeutic effect on LPS-induced macrophage inflammation, which may be related to the increase in PPAR expression.

The inflammation in Chronic Obstructive Pulmonary Disease (COPD) [41] and Myocardial [42] could be regulated by PI3K/Akt pathway. PI3K-dependent phosphorylation of AKT mediates inflammatory signaling in UC [43, 44]. It has been reported that the PI3K/Akt signal transduction pathway plays an important role in the occurrence and development of UC [45], and is involved in reducing the release of cytokines and reducing the inflammatory response. Irisin pretreatment significantly inhibited LPS-induced Akt phosphorylation and increased the expression of PPARα and PPAR γ. Therefore, it is speculated that the therapeutic effect of irisin on inflammation may be related to the increase of PPAR and PI3K/AKT.

Activation of the MAPK signaling pathway is considered to be one of the main factors leading to the release of cytokines and inflammatory mediators in UC [46].

MAPK/Erk and PI3K/Akt pathways have been shown to be upregulated in UC-associated colon cancer[47]. Elevated pERK is observed in a DSS-induced mouse model of UC, suggesting that MAPK signaling is involved in the development of UC [48]. Activation of AKT and ERK enhances protective defenses against oxidative stress and inflammation in colitis [49]. This is consistent with our findings that the phosphorylation of ERK was decreased after pretreatment with Irisin, suggesting that the therapeutic effect of Irisin on LPS-induced macrophage inflammation may be associated with increased ERK expression.

The present study showed that Irisin can modulate the activation of the MAPK pathway, as Irisin pretreatment significantly inhibited the phosphorylation of ERK and AKT and increased the expression of PPAR α and PPAR γ, LPS promotes inflammation and apoptosis in macrophage RAW264.7, whereas Irisin ameliorates this, as validated by flow cytometry and MTT. This study demonstrates that LPS induces inflammation in macrophages and that Irisin has beneficial and anti-inflammatory properties for the development of inflammation-related diseases. This effect may be mediated by the MAPK signaling pathway, and further research is needed to block the proteins associated with the signaling pathway.

Acknowledgments

The authors would like to thank Xuhong Lin, Yukuan Du, Jingnan Yang, Qiaoling He, Huichao Wang for their contributions to the paper.

Author contribution

All authors contributed to the study’s conception and design. Xuhong Lin, Yukuan Du, Huichao Wang, Jingnan Yang, and Yuke Ma collected samples and clinical information. Data were analyzed by Jingnan Yang and Huichao Wang. Qiaoling He and Yukuan Du analyzed and interpreted the data. The first draft of the manuscript was written by Yuke Ma. Xuhong Lin and Yuke Ma revised the manuscript. All authors had full access to the final version of the report and agreed to the submission.

Funding

This work was supported by the Projects supported by the National Natural Science Foundation of China (81500430, U1304802), the Science and Technology Planning Project to Henan Province (192102310045), Medical science and Technology Project of Henan Province (2018020320).

Conflict of interest

The authors declare that there are no conflicts of interest.

Ethical approval

This study does not involve humans or animals and does not require ethical approval.

Consent for publication

Its publication has been approved by all author.

Data availability

The datasets during the current study are available from the corresponding author on reasonable request.

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Anti-inflammatory effects of Irisin in LPS-stimulated RAW264.7 macrophages by inhibiting the MAPK pathway

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