Immunoproteasome inhibitor DPLG3 attenuates experimental colitis by restraining NF-κB activation

Moallemian, Rezvan; Rehman, Ashfaq Ur; Zhao, Na; Wang, Huan; Chen, Haifeng; Lin, Gang; Ma, Xiaojing; Yu, Jing

doi:10.1016/j.bcp.2020.113964

Cited by 15 publications

(6 citation statements)

References 38 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…However, the expression of LMP7 in hematopoietic cells (but not other cells such as IEC) was critical for colitis development ( 57 ), suggesting differential roles of the immunoproteasome in different cell types. Moreover, other major functions of immunoproteasomes such as the protection from oxidative stress and oxidation-induced cell death ( 58 , 59 ) as well as a role in NF-κB activation ( 55 , 60 ) have been described. Therefore, the functional consequence of IL-27-induced immunoproteasome upregulation and increased antigen processing in IEC needs to be further defined.…”

Section: Discussionmentioning

confidence: 99%

Identification of IL-27 as a novel regulator of major histocompatibility complex class I and class II expression, antigen presentation, and processing in intestinal epithelial cells

Diegelmann,

Brand

2023

Front. Immunol.

View full text Add to dashboard Cite

Antigen presentation via major histocompatibility complex (MHC) class I and class II receptors plays a fundamental role in T cell-mediated adaptive immunity. A dysregulation of this fine-tuned recognition might result in the development of autoimmune diseases such as inflammatory bowel diseases that are characterized by chronic relapsing inflammation of the intestinal tract and a damaged intestinal epithelial barrier. While MHCII receptors are usually expressed by professional antigen presenting cells (APC) only, there is increasing evidence that non-immune cells such as intestinal epithelial cells (IEC) might express MHCII upon stimulation with IFN-γ and thus act as non-professional APC. However, little is known about other factors regulating intestinal epithelial MHC expression. Here, we identify IL-27 as an inducer of different MHCI and MHCII receptor subtypes and the invariant chain (CD74/li) in IEC via the STAT1/IRF1/CIITA axis. CIITA, MHCII, and CD74 expression was significantly increased in IEC from Crohn’s disease (CD) patients with active disease compared to controls or CD patients in remission. IEC phagocytosed and digested external antigens and apoptotic cells. IL-27 strongly stimulated antigen processing via the immunoproteasome in a IRF1-dependent manner. In co-culture experiments, antigen-primed IEC strongly enhanced lymphocyte proliferation and IL-2 secretion, dependent on direct cell-cell contact. IL-27 pretreatment of IEC significantly increased CD4+ T cell proliferation and reduced IL-2 levels in lymphocytes in coculture. In summary, we identified IL-27 as a novel regulator of IEC antigen processing and presentation via MHCI and MHCII receptors, underscoring the importance of IEC as non-professional APC.

show abstract

Section: Discussionmentioning

confidence: 99%

Identification of IL-27 as a novel regulator of major histocompatibility complex class I and class II expression, antigen presentation, and processing in intestinal epithelial cells

Diegelmann,

Brand

2023

Front. Immunol.

View full text Add to dashboard Cite

show abstract

“…However, before the immunoproteasome becomes a therapeutic target in IgAN, further research is necessary to clarify whether and how the immunoproteasome participate in pathogenesis and/or progression of the disease. The advantages and disadvantages of immunoproteasome as a therapeutic target are summarized in Table 1 [60][61][62][63][64][65][66][67]. More basic studies on immunoproteasome structure and functions are needed to guide immunoproteasome-specific therapy [66,67] Influence on some physiological processes Apart from immune response, immunoproteasome is involved in some physiological processes such as protein degradation, cell proliferation and survival…”

Section: The Immunoproteasome As a Therapeutic Targetmentioning

confidence: 99%

Immunoproteasome in IgA Nephropathy: State-of-Art and Future Perspectives

Gan

Zhou³

et al. 2020

Int. J. Biol. Sci.

View full text Add to dashboard Cite

IgA nephropathy (IgAN) is a leading cause of chronic kidney disease and renal failure. The exact pathogenesis of IgAN is not well defined, but some genetic studies have led to a novel discovery that the immunoproteasome probably plays an important role in IgAN. The immunoproteasome is a proteasome variant that is expressed when cells are stressed or receive inflammatory signals. While immunoproteasome is suggested to be mainly involved in major histocompatibility complex-I (MHC-I) antigen presentation, recent studies indicate that it may assert broad functions in trafficking events that activate both innate and adaptive immunity. In this review, we first summarize new insights into its functions in immunity, and discuss how it underlies its associations with IgAN. We also highlight its potential as a therapeutic target for the future.

show abstract

“…Furthermore, inhibition of LMP2 by shRNA showed the suppression of neuroinflammation response and reduced infarction volume [ 3 ].Similarly, Administration of a high selective proteasome inhibitor PR-957 or LMP7 gene knockout significantly attenuates inflammatory cytokines secretion and disease manifestation observed in animal experimental models of autoimmune encephalomyelitis and rheumatoid arthritis [ 4 , 5 ]. Taken together, these findings suggest a key role for the immunoproteasome participating in innate immune response and regulation of inflammatory cytokines, which possibly involves in compromised NF-κB signaling or NF-κB-independent signal pathways [ 6 , 7 ].…”

Section: Introductionmentioning

confidence: 99%

LMP2 deficiency causes abnormal metabolism, oxidative stress, neuroinflammation, myelin loss and neurobehavioral dysfunctions

et al. 2023

View full text Add to dashboard Cite

Background Substantial evidence suggests that immunoproteasome is implicated in the various neurological diseases such as stroke, multiple sclerosis and neurodegenerative diseases. However, whether the immunoproteasome itself deficiency causes brain disease is still unclear. Therefore, the aim of this study was to explore the contribution of the immunoproteasome subunit low molecular weight protein 2 (LMP2) in neurobehavioral functions. Methods Male LMP2 gene completed knockout (LMP2-KO) and littermate wild type (WT) Sprague–Dawley (SD) rats aged 12-month-old were used for neurobehavioral testing and detection of proteins expression by western blotting and immunofluorescence. A battery of neurobehavioral test tools including Morris water maze (MWM), open field maze, elevated plus maze were used to evaluate the neurobehavioral changes in rats. Evans blue (EB) assay, Luxol fast blue (LFB) and Dihydroethidium (DHE) staining were applied to explore the blood–brain barrier (BBB) integrity, brain myelin damage and brain intracellular reactive oxygen species (ROS) levels, respectively. Results We firstly found that LMP2 gene deletion did not cause significantly difference in rats’ daily feeding activity, growth and development as well as blood routine, but it led to metabolic abnormalities including higher levels of low-density lipoprotein cholesterol, uric acid and blood glucose in the LMP2-KO rats. Compared with the WT rats, LMP2-KO rats displayed obviously cognitive impairment and decreased exploratory activities, increased anxiety-like behavior and without strong effects on gross locomotor abilities. Furthermore, multiple myelin loss, increased BBB leakage, downregulation of tight junction proteins ZO-1, claudin-5 and occluding, and enhanced amyloid-β protein deposition were observed in brain regions of LMP2-KO rats. In addition, LMP2 deficiency significantly enhanced oxidative stress with elevated levels of ROS, caused the reactivation of astrocytes and microglials and markedly upregulated protein expression levels of interleukin (IL)-1 receptor-associated kinase 1 (IRAK1), IL-6 and tumor necrosis factor-α (TNF-α) compared to the WT rats, respectively. Conclusion These findings highlight LMP2 gene global deletion causes significant neurobehavioral dysfunctions. All these factors including metabolic abnormalities, multiple myelin loss, elevated levels of ROS, increased BBB leakage and enhanced amyloid-β protein deposition maybe work together and eventually led to chronic oxidative stress and neuroinflammation response in the brain regions of LMP2-KO rats, which contributed to the initial and progress of cognitive impairment.

show abstract

Immunoproteasome inhibitor DPLG3 attenuates experimental colitis by restraining NF-κB activation

Cited by 15 publications

References 38 publications

Identification of IL-27 as a novel regulator of major histocompatibility complex class I and class II expression, antigen presentation, and processing in intestinal epithelial cells

Identification of IL-27 as a novel regulator of major histocompatibility complex class I and class II expression, antigen presentation, and processing in intestinal epithelial cells

Immunoproteasome in IgA Nephropathy: State-of-Art and Future Perspectives

LMP2 deficiency causes abnormal metabolism, oxidative stress, neuroinflammation, myelin loss and neurobehavioral dysfunctions

Contact Info

Product

Resources

About