Deleting MyD88 signaling in myeloid cells promotes development of adenocarcinomas of the colon

Song, Junhua; Chen, Zhengtao; Geng, Tingting; Wang, Mei‐Xiang; Yi, Shuying; Li, Kai; Zhou, Wei; Gao, Jiming; Song, Wengang; Tang, Hua

doi:10.1016/j.canlet.2018.06.036

Cited by 8 publications

(9 citation statements)

References 55 publications

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“…Additionally, deletion of MyD88 would be harmful to the host because myeloid cells would lose the capacity to respond to microbial ligands through the TLR signaling pathway. There would be defective phagocytosis, and a lack of clearance of any commensal bacteria that get across the epithelium in addition to impaired IL-1R signaling pathway due to lack of upregulation of inflammasome machinery and production of IL-1β ( Song et al, 2018b ; Gasse et al, 2007 ; Marr et al, 2003 ). Thus, our investigation specifically teases out the function of IEC-intrinsic IL-1R signaling allowing us to conclude that it contributes to pathology during acute inflammatory colitis.…”

Section: Discussionmentioning

confidence: 99%

IEC-intrinsic IL-1R signaling holds dual roles in regulating intestinal homeostasis and inflammation

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Meibers

Eshleman

et al. 2023

Journal of Experimental Medicine

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Intestinal epithelial cells (IECs) constitute a critical first line of defense against microbes. While IECs are known to respond to various microbial signals, the precise upstream cues regulating diverse IEC responses are not clear. Here, we discover a dual role for IEC-intrinsic interleukin-1 receptor (IL-1R) signaling in regulating intestinal homeostasis and inflammation. Absence of IL-1R in epithelial cells abrogates a homeostatic antimicrobial program including production of antimicrobial peptides (AMPs). Mice deficient for IEC-intrinsic IL-1R are unable to clear Citrobacter rodentium (C. rodentium) but are protected from DSS-induced colitis. Mechanistically, IL-1R signaling enhances IL-22R–induced signal transducer and activator of transcription 3 (STAT3) phosphorylation in IECs leading to elevated production of AMPs. IL-1R signaling in IECs also directly induces expression of chemokines as well as genes involved in the production of reactive oxygen species. Our findings establish a protective role for IEC-intrinsic IL-1R signaling in combating infections but a detrimental role during colitis induced by epithelial damage.

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Section: Discussionmentioning

confidence: 99%

IEC-intrinsic IL-1R signaling holds dual roles in regulating intestinal homeostasis and inflammation

Overcast

Meibers

Eshleman

et al. 2023

Journal of Experimental Medicine

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“…The absence of MyD88 activated the Wnt and STAT3 pathways, resulting in more β-catenin gene mutations and less DNA repair, thereby promoting the development of colon cancer. 372 TLRs in myeloid cells remodel the TME. The deletion of MyD88 in myeloid cells caused an increase in Foxp3 + Tregs, and IL-1β-producing neutrophils, and reduced IFN-γ expression by CTL.…”

Section: Innate Immune Pathways In Cancermentioning

confidence: 99%

Harnessing innate immune pathways for therapeutic advancement in cancer

Hu,

Sun,

Lin

et al. 2024

Sig Transduct Target Ther

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The innate immune pathway is receiving increasing attention in cancer therapy. This pathway is ubiquitous across various cell types, not only in innate immune cells but also in adaptive immune cells, tumor cells, and stromal cells. Agonists targeting the innate immune pathway have shown profound changes in the tumor microenvironment (TME) and improved tumor prognosis in preclinical studies. However, to date, the clinical success of drugs targeting the innate immune pathway remains limited. Interestingly, recent studies have shown that activation of the innate immune pathway can paradoxically promote tumor progression. The uncertainty surrounding the therapeutic effectiveness of targeted drugs for the innate immune pathway is a critical issue that needs immediate investigation. In this review, we observe that the role of the innate immune pathway demonstrates heterogeneity, linked to the tumor development stage, pathway status, and specific cell types. We propose that within the TME, the innate immune pathway exhibits multidimensional diversity. This diversity is fundamentally rooted in cellular heterogeneity and is manifested as a variety of signaling networks. The pro-tumor effect of innate immune pathway activation essentially reflects the suppression of classical pathways and the activation of potential pro-tumor alternative pathways. Refining our understanding of the tumor’s innate immune pathway network and employing appropriate targeting strategies can enhance our ability to harness the anti-tumor potential of the innate immune pathway and ultimately bridge the gap from preclinical to clinical application.

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“…MyD88 signalling is involved in the advancement of CAC in colonic myeloid cells. Intestinal myeloid cells are important for maintaining local homeostasis and have a major role in regulating the existence of colitis and CAC [ 104 ]. MyD88 deletion also causes an increase in mucosal expression of COX-2, p-STAT3, β-catenin, and cyclinD1; all of which are associated with further DNA damage and β-catenin mutation.…”

Section: Inflammatory Mediators In Inflammatory Bowel Diseasementioning

confidence: 99%

“…In addition, MyD88 knockout mice infected with Salmonella Typhimurium endured enhanced intestinal tissue loss and showed barrier disruption, compared to wild-type mice [ 106 ]. Thus, myeloid MyD88 signalling protects the intestine from inflammation as well as tumourigenesis during the development of CAC [ 104 ].…”

Section: Inflammatory Mediators In Inflammatory Bowel Diseasementioning

confidence: 99%

Cancer Immunotherapy: The Checkpoint between Chronic Colitis and Colorectal Cancer

Ephraim

Feehan

Fraser

et al. 2022

Cancers

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Inflammatory Bowel Disease (IBD) is a group of diseases that cause intestinal inflammation and lesions because of an abnormal immune response to host gut microflora. Corticosteroids, anti-inflammatories, and antibiotics are often used to reduce non-specific inflammation and relapse rates; however, such treatments are ineffective over time. Patients with chronic colitis are more susceptible to developing colorectal cancer, especially those with a longer duration of colitis. There is often a limit in using chemotherapy due to side effects, leading to reduced efficacy, leaving an urgent need to improve treatments and identify new therapeutic targets. Cancer immunotherapy has made significant advances in recent years and is mainly categorized as cancer vaccines, adoptive cellular immunotherapy, or immune checkpoint blockade therapies. Checkpoint markers are expressed on cancer cells to evade the immune system, and as a result checkpoint inhibitors have transformed cancer treatment in the last 5–10 years. Immune checkpoint inhibitors have produced long-lasting clinical responses in both single and combination therapies. Winnie mice are a viable model of spontaneous chronic colitis with immune responses like human IBD. Determining the expression levels of checkpoint markers in tissues from these mice will provide insights into disease initiation, progression, and cancer. Such information will lead to identification of novel checkpoint markers and the development of treatments with or without immune checkpoint inhibitors or vaccines to slow or stop disease progression.

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Deleting MyD88 signaling in myeloid cells promotes development of adenocarcinomas of the colon

Cited by 8 publications

References 55 publications

IEC-intrinsic IL-1R signaling holds dual roles in regulating intestinal homeostasis and inflammation

IEC-intrinsic IL-1R signaling holds dual roles in regulating intestinal homeostasis and inflammation

Harnessing innate immune pathways for therapeutic advancement in cancer

Cancer Immunotherapy: The Checkpoint between Chronic Colitis and Colorectal Cancer

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