How autophagy, a potential therapeutic target, regulates intestinal inflammation

Chen, Shuang-Lan; Li, Chunmeng; Li, Wei; Liu, Qingsong; Hu, Shuangyuan; Zhao, Maoyuan; Hu, Dong-Sen; Hao, Yanwei; Zeng, Jinhao; Zhang, Yi

doi:10.3389/fimmu.2023.1087677

Cited by 10 publications

(5 citation statements)

References 193 publications

(235 reference statements)

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“…The implication of autophagy in CD is multifaceted and cell-specific [36,243]. As mentioned before, dysfunctional autophagy in IECs increases the expression of claudin-2 due to reduced lysosomal degradation and the permeability of the intestinal barrier is in-creased [106,244].…”

Section: Role Of Autophagy In CDmentioning

confidence: 85%

Autophagy and Apoptosis in Inflammatory Bowel Disease

Kouroumalis,

Tsomidis,

Voumvouraki

2023

Gastroenterology Insights

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The pathogenesis of inflammatory bowel disease (IBD) implicates several interconnecting factors. Immunity and external factors interact, and most aspects are still under investigation. Autophagy and apoptosis are two critical pathways that decide the fate of the individual cells of the intestinal mucosa. Experimental and clinical data indicate that the two are closely interconnected and usually mutually exclusive. However, despite the abundant information on their role, very limited translation into therapeutic application has been seen during recent years. In this review, research on these two pathways is presented. After a general overview of autophagy and apoptosis, their association with IBD, including the important mitophagy and ferroptosis, is discussed. The influence of autophagy- and apoptosis-related genes is also discussed. Finally, the interplay of autophagy and apoptosis in IBD is presented and the implications for treatment applications are examined. It is shown that dysregulated autophagy leads to increased apoptosis of enterocytes and impairs the tight junction proteins of the protective intestinal barrier. Dysregulated autophagy also induces the downregulation of lysozyme and the other antimicrobial proteins’ production. Mucus production by the goblet cells is also reduced due to defective autophagy and increased apoptosis.

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Section: Role Of Autophagy In CDmentioning

confidence: 85%

Autophagy and Apoptosis in Inflammatory Bowel Disease

Kouroumalis,

Tsomidis,

Voumvouraki

2023

Gastroenterology Insights

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“…Beclin1 is an essential autophagy-related protein. Considering that autophagy has been illustrated to be closely associated with the progression of IBD [ 28 , 29 ], whether YTHDC1 participates in regulating autophagy remains to be confirmed. Previous studies have reported that knockdown of YTHDC1 leads to inhibition of autophagy in keratinocytes [ 23 ], and loss of YTHDC1 has an inhibitory effect on mitophagy, which was identified as a biomarker of hypertrophic cardiomyopathy [ 30 ].…”

Section: Discussionmentioning

confidence: 99%

YTHDC1 inhibits autophagy-dependent NF-κB signaling by stabilizing Beclin1 mRNA in macrophages

Zhou,

Zhang,

et al. 2024

J Inflamm

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Background YTHDC1, a key m(6)A nuclear reader, plays a crucial role in regulating mRNA splicing, export, and stability. However, the functional significance and regulatory mechanisms of YTHDC1 in inflammatory bowel disease (IBD) remain to be explored. Methods We established a dextran sulfate sodium (DSS)-induced murine colitis model in vivo and LPS/IFN-γ-stimulated macrophage inflammation in vitro. The expression of YTHDC1 was determined. Colocalization of YTHDC1 and macrophages was assayed by immunofluorescence staining. LV-YTHDC1 or shYTHDC1 lentiviruses were applied for YTHDC1 overexpression or inhibition. For NF-κB inhibition, JSH-23 was utilized. The interaction of YTHDC1 and Beclin1 mRNA was determined by RIP, and the m6A modification of Beclin1 was confirmed by MeRIP. Results In DSS-induced colitis and LPS/IFN-γ-treated RAW264.7 macrophages, we observed a significant downregulation of YTHDC1. Overexpression of YTHDC1 resulted in decreased levels of iNOS, CD86, and IL-6 mRNA, along with inhibited NF-κB activation in LPS/IFN-γ-treated RAW264.7 cells. Conversely, downregulation of YTHDC1 promoted iNOS expression and inhibited autophagy. Additionally, the effect of YTHDC1 knockdown on CD86 and IL-6 mRNA induced by LPS/IFN-γ was abolished by the NF-κB inhibitor JSH-23. Mechanistically, YTHDC1 interacted with Beclin1 mRNA, thereby stabilizing Beclin1 mRNA and enhancing Beclin1 expression and autophagy. These effects ultimately led to the inhibition of NF-κB signaling in LPS/IFN-γ-challenged macrophages. Conclusions YTHDC1 inhibited the macrophage-mediated inflammatory response by stabilizing Beclin1 mRNA, which may be a potential therapeutic target for the treatment of IBD.

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“…Traditionally, it has been believed that gut inflammation has been only promoted by T helper cells (Th) 1, Th2, Th17 and Tregs, but now we known that inflammation is also induced by other immune cells, cytokines and processes, including macrophages, DCs, tumor necrosis factor (TNF), inflammasome activation, or autophagy ( 113 – 117 ). Particularly, autophagy deficiency decreases antigen sampling, increases DC maturation, and promotes pro-inflammatory DCs ( 118 ). Atg16l1 autophagy gene deficiency promotes the bacterial translocation of DSS-induced colitis in vivo and regulates autophagy and phagocytosis, which lead to an exacerbation of the intestinal inflammation ( 119 ).…”

Section: Dcs and Inflammatory Bowel Diseasementioning

confidence: 99%

Dendritic cells: the yin and yang in disease progression

Jiménez-Cortegana,

Palomares,

Alba

et al. 2024

Front. Immunol.

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Dendritic cells (DCs) are antigen presenting cells that link innate and adaptive immunity. DCs have been historically considered as the most effective and potent cell population to capture, process and present antigens to activate naïve T cells and originate favorable immune responses in many diseases, such as cancer. However, in the last decades, it has been observed that DCs not only promote beneficial responses, but also drive the initiation and progression of some pathologies, including inflammatory bowel disease (IBD). In line with those notions, different therapeutic approaches have been tested to enhance or impair the concentration and role of the different DC subsets. The blockade of inhibitory pathways to promote DCs or DC-based vaccines have been successfully assessed in cancer, whereas the targeting of DCs to inhibit their functionality has proved to be favorable in IBD. In this review, we (a) described the general role of DCs, (b) explained the DC subsets and their role in immunogenicity, (c) analyzed the role of DCs in cancer and therapeutic approaches to promote immunogenic DCs and (d) analyzed the role of DCs in IBD and therapeutic approaches to reduced DC-induced inflammation. Therefore, we aimed to highlight the “yin-yang” role of DCs to improve the understand of this type of cells in disease progression.

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How autophagy, a potential therapeutic target, regulates intestinal inflammation

Cited by 10 publications

References 193 publications

Autophagy and Apoptosis in Inflammatory Bowel Disease

Autophagy and Apoptosis in Inflammatory Bowel Disease

YTHDC1 inhibits autophagy-dependent NF-κB signaling by stabilizing Beclin1 mRNA in macrophages

Dendritic cells: the yin and yang in disease progression

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