The Loss of YTHDC1 in Gut Macrophages Exacerbates Inflammatory Bowel Disease

Ge, Xuejun; Gang, Xue; Ding, Yan; Li, Ran; Hu, Kaining; Xu, Tengjiao; Sun, Min; Zhao, Bin; Wen, Chuangyu; Du, Jie

doi:10.1002/advs.202205620

Cited by 10 publications

(6 citation statements)

References 47 publications

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“…On the one hand, they produce an overabundance of inflammatory mediators, which prolongs the inflammatory response. On the other hand, macrophages not only form a defense line against infections, but also stimulates tissue repair and regeneration following injury [ 93 , 184 ]. m6A modification can impact the polarization of M1 and M2 macrophages, influencing the inflammatory response and intestinal epithelial integrity.…”

Section: Discussion and Perspectivesmentioning

confidence: 99%

“…The mechanism through which the gut microbiota controls the host’s m6A methylome at the molecular level is becoming increasingly clear. Recently, research has indicated that microbiota originating from either IBD patients or mice can decrease the expression of YTHDC1 in macrophages situated in the intestines, consequently expediting the development of IBD in animal models [ 93 ]. Building upon these discoveries, it can be deduced that the gut microbiota orchestrates host m6A modifications through a multifaceted approach: furnishing m6A modification donors and generating various microbial metabolites or toxins.…”

Section: Microbial Barrier and M6amentioning

confidence: 99%

“…Recent research has revealed that METTL14 mediates the m6A modification of Rhoh mRNA at positions 603–607 nt and 616–620 nt, as well as Nme1 mRNA at positions 497-501nt and 590-594nt. Moreover, YTHDC1 promotes Rhoh expression to suppress inflammatory responses and enhances Nme1 expression to strengthen the integrity of the colonic epithelial barrier, dependent on the METTL14/m6A pathway [ 93 ]. Additionally, the evidence highlights the significant involvement of IGF2BP2 in macrophage activation during the development of colitis induced by DSS.…”

Section: Immune Barrier Of the Intestine And M6amentioning

confidence: 99%

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Nurturing gut health: role of m6A RNA methylation in upholding the intestinal barrier

Wang,

Yang,

Jiang

et al. 2024

Cell Death Discov.

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The intestinal lumen acts as a critical interface connecting the external environment with the body’s internal state. It’s essential to prevent the passage of harmful antigens and bacteria while facilitating nutrient and water absorption. The intestinal barriers encompass microbial, mechanical, immunological, and chemical elements, working together to maintain intestinal balance. Numerous studies have associated m6A modification with intestinal homeostasis. This review comprehensively outlines potential mechanisms through which m6A modification could initiate, exacerbate, or sustain barrier damage from an intestinal perspective. The pivotal role of m6A modification in preserving intestinal equilibrium provides new insights, guiding the exploration of m6A modification as a target for optimizing preventive and therapeutic strategies for intestinal homeostasis.

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Section: Discussion and Perspectivesmentioning

confidence: 99%

Section: Microbial Barrier and M6amentioning

confidence: 99%

Section: Immune Barrier Of the Intestine And M6amentioning

confidence: 99%

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Nurturing gut health: role of m6A RNA methylation in upholding the intestinal barrier

Wang,

Yang,

Jiang

et al. 2024

Cell Death Discov.

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“…YTHDC1 has been linked to the resolution of inflammation and restoration of colonic epithelial barrier function in patients with inflammatory bowel disease. It inhibited macrophage inflammation by regulating Ras homolog family member H (RHOH) [22]. IGF2BP2 was also found to convert M1 macrophages to M2 by an action on tuberous sclerosis 1 ( Tsc1 ) and peroxisome proliferator-activated receptor-γ ( Ppar-γ ) during the development of dextran sulfate sodium-induced colitis [23].…”

Section: M6a Modification In Monocytes/macrophagesmentioning

confidence: 99%

N6-Methyladenosine (m6A) Modification in Natural Immune Cell-Mediated Inflammatory Diseases

Teng,

Yi,

Chen

et al. 2023

J Innate Immun

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The post-transcriptional N6-methyladenosine (m6A) modification of RNA influences stability, transport, and translation with implications for various physiological and pathological processes. Immune cell development, differentiation, and activation are also thought to be regulated by m6A and affect host defense against pathogens and inflammatory response with impacts on infectious, neoplastic, autoimmune, cardiovascular, hepatic, and osteal diseases. The current review summarizes recent research on m6A in monocyte/macrophages, neutrophils, dendritic cells, natural killer cells, and microglia and gives insights into epigenetic modifications of the immune system and novel therapeutic strategies for immune-related diseases.

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“…Another study reveals that YTHDC1 is crucial to maintain islet β-cell function, deficiency of which results in diabetes [ 18 ]. In addition, YTHDC1 participates in the epithelial repair of the colon by regulating Rhoh and Nme1 expression [ 19 ]. m(6)A is believed to affect cellular processes, including autophagy [ 20 ].…”

Section: Introductionmentioning

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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The Loss of YTHDC1 in Gut Macrophages Exacerbates Inflammatory Bowel Disease

Cited by 10 publications

References 47 publications

Nurturing gut health: role of m6A RNA methylation in upholding the intestinal barrier

Nurturing gut health: role of m6A RNA methylation in upholding the intestinal barrier

N6-Methyladenosine (m6A) Modification in Natural Immune Cell-Mediated Inflammatory Diseases

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

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