TIPE2 May Target the Nrf2/HO-1 Pathway to Inhibit M1 Macrophage–Related Neutrophilic Inflammation in Asthma

Shi, Bingqing; Hao, Yuqiu; Li, Wei; Dong, Hongna; Xu, Mengting; Gao, Peng

doi:10.3389/fimmu.2022.883885

Cited by 9 publications

(2 citation statements)

References 41 publications

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“…Consistent with the above studies, our study revealed that patients with obese asthma had significantly higher numbers of neutrophils in induced sputum and a higher level of serum leptin than patients with nonobese asthma. M1 macrophage-associated cytokines (IL-6 and TNF-α) were elevated in the sputum of patients with neutrophilic asthma (Shi et al 2022 ). Leptin was found to participate in the inflammatory response by targeting macrophages (Mancuso et al 2004 ; Raso et al 2002 ).…”

Section: Discussionmentioning

confidence: 99%

Leptin/obR signaling exacerbates obesity-related neutrophilic airway inflammation through inflammatory M1 macrophages

Wang

Wan

2023

Mol Med

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Background Obesity-related asthma is a kind of nonallergic asthma with excessive neutrophil infiltration in the airways. However, the underlying mechanisms have been poorly elucidated. Among the adipokines related to obesity, leptin is related to the inflammatory response. However, little is understood about how leptin acts on the leptin receptor (obR) in neutrophilic airway inflammation in obesity-associated asthma. We explored the inflammatory effects of leptin/obR signaling in an obesity-related neutrophilic airway inflammation mouse model. Methods We established a neutrophilic airway inflammation mouse model using lipopolysaccharide (LPS)/ovalbumin (OVA) sensitization and OVA challenge (LPS + OVA/OVA) in lean, obese, or db/db (obR deficiency) female mice. Histopathological, bronchoalveolar lavage fluid (BALF) inflammatory cell, and lung inflammatory cytokine analyses were used to analyze airway inflammation severity. Western blotting, flow cytometry, reverse transcription‐polymerase chain reaction (RT-PCR), and enzyme-linked immunosorbent assay (ELISA) were used to evaluate the underlying mechanisms. In vitro bone marrow‐derived macrophage (BMDM) and bone marrow-derived neutrophil experiments were performed. Results We found that the serum leptin level was higher in obese than in lean female mice. Compared to LPS/OVA + OVA-treated lean female mice, LPS/OVA + OVA-treated obese female mice had higher peribronchial inflammation levels, neutrophil counts, Th1/Th17-related inflammatory cytokine levels, M1 macrophage polarization levels, and long isoform obR activation, which could be decreased by the obR blockade (Allo-Aca) or obR deficiency, suggesting a critical role of leptin/obR signaling in the pathogenesis of obesity-related neutrophilic airway inflammation in female mice. In in vitro experiments, leptin synergized with LPS/IFN-γ to promote the phosphorylation of the long isoform obR and JNK/STAT3/AKT signaling pathway members to increase M1 macrophage polarization, which was reversed by Allo-Aca. Moreover, leptin/obR-mediated M1 macrophage activity significantly elevated CXCL2 production and neutrophil recruitment by regulating the JNK/STAT3/AKT pathways. In clinical studies, obese patients with asthma had higher serum leptin levels and M1 macrophage polarization levels in induced sputum than non-obese patients with asthma. Serum leptin levels were positively correlated with M1 macrophage polarization levels in patients with asthma. Conclusions Our results demonstrate leptin/obR signaling plays an important role in the pathogenesis of obesity-related neutrophilic airway inflammation in females by promoting M1 macrophage polarization. Graphical abstract

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Section: Discussionmentioning

confidence: 99%

Leptin/obR signaling exacerbates obesity-related neutrophilic airway inflammation through inflammatory M1 macrophages

Wang

Wan

2023

Mol Med

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“…TIPE2 is preferentially expressed in lymphoid tissues, and its deletion leads to lethal Toll-like receptor and T cell receptor activation, multiorgan inflammation, splenomegaly, and premature death. 7 TIPE2 inhibits M1 macrophage-related neutrophilic inflammation in asthma 8 and accelerates IL-4-induced immunomodulatory M2 differentiation. 9 Decreased TIPE2 in peripheral blood mononuclear cells is associated with the disease progression of chronic hepatitis, 10 asthma, 11 systemic lupus erythematosus, 12 and osteoporosis.…”

Section: Introductionmentioning

confidence: 99%

TIPE2 regulates periodontal inflammation by inhibiting NF-κB p65 phosphorylation

Liu

Sheng

et al. 2023

J. Appl. Oral Sci.

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TIPE2 regulates periodontal inflammation by inhibiting NF-κB p65 phosphorylationThe roles and molecular mechanisms of tumor necrosis factor-α-induced protein 8-like 2 (TIPE2) in periodontitis remain largely unknown. Objective:This study aimed to determine the expression of TIPE2 and NF-κB p65 in rat Porphyromonas gingivalis-induced periodontics in vivo. Methodology: Periodontal inflammation and alveolar bone resorption were analyzed using western blotting, micro-computed tomography, TRAP staining, immunohistochemistry, and immunofluorescence. THP-1 monocytes were stimulated using 1 μg/ml Pg. lipopolysaccharide (Pg.LPS) to determine the expression of TIPE2 in vitro. TIPE2 mRNA was suppressed by siRNA transfection, and the transfection efficiency was proven using western blotting and real-time PCR. The NF-κB pathway was activated by treating the cells with 1 μg/ml Pg.LPS to explore related mechanisms. Results: The expression of both TIPE2 and NF-κB p65 was increased in the gingival tissues of rat periodontitis compared with normal tissues. Positive expression of TIPE2 was distributed in inflammatory infiltrating cells and osteoclasts in the marginal lacunae of the alveolar bone. However, strong positive expression of TIPE2 in THP-1 was downregulated after Pg.LPS stimulation. TIPE2 levels negatively correlated with TNF-α and IL-1β. Decreased TIPE2 in THP-1 further promoted NF-κB p65 phosphorylation. Mechanistically, TIPE2 knockdown upregulated NF-κB signaling pathway activity. Conclusions: Taken together, these findings demonstrate that TIPE2 knockdown aggravates periodontal inflammatory infiltration via NF-κB pathway. Interventions aimed at increasing TIPE2 may help in the therapeutic applications for periodontitis.

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Targeting Immunoproteasome in Polarized Macrophages Ameliorates Experimental Emphysema Via Activating NRF1/2‐P62 Axis and Suppressing IRF4 Transcription

Guo,

Shi,

Jiang

et al. 2024

Advanced Science

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Chronic obstructive pulmonary disease (COPD) stands as the prevailing chronic airway ailment, characterized by chronic bronchitis and emphysema. Current medications fall short in treatment of these diseases, underscoring the urgent need for effective therapy. Prior research indicated immunoproteasome inhibition alleviated various inflammatory diseases by modulating immune cell functions. However, its therapeutic potential in COPD remains largely unexplored. Here, an elevated expression of immunoproteasome subunits LMP2 and LMP7 in the macrophages isolated from mouse with LPS/Elastase‐induced emphysema and polarized macrophages in vitro is observed. Subsequently, intranasal administration of the immunoproteasome‐specific inhibitor ONX‐0914 significantly mitigated COPD‐associated airway inflammation and improved lung function in mice by suppressing macrophage polarization. Additionally, ONX‐0914 capsulated in PLGA nanoparticles exhibited more pronounced therapeutic effect on COPD than naked ONX‐0914 by targeting immunoproteasome in polarized macrophages. Mechanistically, ONX‐0914 activated autophagy and endoplasmic reticulum (ER) stress are not attribute to the ONX‐0914 mediated suppression of macrophage polarization. Intriguingly, ONX‐0914 inhibited M1 polarization through the nuclear factor erythroid 2‐related factor‐1 (NRF1) and NRF2‐P62 axis, while the suppression of M2 polarization is regulated by inhibiting the transcription of interferon regulatory factor 4 (IRF4). In summary, the findings suggest that targeting immunoproteasome in macrophages holds promise as a therapeutic strategy for COPD.

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TIPE2 May Target the Nrf2/HO-1 Pathway to Inhibit M1 Macrophage–Related Neutrophilic Inflammation in Asthma

Cited by 9 publications

References 41 publications

Leptin/obR signaling exacerbates obesity-related neutrophilic airway inflammation through inflammatory M1 macrophages

Leptin/obR signaling exacerbates obesity-related neutrophilic airway inflammation through inflammatory M1 macrophages

TIPE2 regulates periodontal inflammation by inhibiting NF-κB p65 phosphorylation

Targeting Immunoproteasome in Polarized Macrophages Ameliorates Experimental Emphysema Via Activating NRF1/2‐P62 Axis and Suppressing IRF4 Transcription

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