Enhanced Mucosal Defense and Reduced Tumor Burden in Mice with the Compromised Negative Regulator IRAK-M

Rothschild, Daniel E.; Zhang, Yao; Diao, Na; Lee, Christina K.; Chen, Keqiang; Caswell, Clayton C.; Slade, Daniel J.; Helm, Richard F.; LeRoith, Tanya; Li, Liwu; Allen, Irving C.

doi:10.1016/j.ebiom.2016.11.039

Cited by 20 publications

(42 citation statements)

References 46 publications

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“…Interestingly, in these initial studies, Irak-m −/− mice do not display enhanced morbidity or mortality following infection, despite the increased inflammation [47]. These findings are consistent with a more recent study that showed the Irak-m −/− mice are protected in models of experimental colitis and colitis associated tumorigenesis [56]. Mice lacking IRAK-M were found to have a robust immune response to bacteria translocating from the lumen following chemical induced damage to the intestinal epithelial cell barrier [56].…”

Section: Transcription Inhibitionsupporting

confidence: 82%

“…Mice lacking IRAK-M were found to have a robust immune response to bacteria translocating from the lumen following chemical induced damage to the intestinal epithelial cell barrier [56]. The attenuation in pathogenesis was associated with large expansions of gastrointestinal associated lymphoid tissue (GALT), increased neutrophil function, and enhanced T-cell recruitment [56]. Complementary data revealed that the gastrointestinal (GI) tract of the Irak-m −/− mice had a lower total colonic bacterial load compared to wild type counterparts, which could also contribute to attenuation of disease pathogenesis [57].…”

Section: Transcription Inhibitionmentioning

confidence: 99%

“…While these data are certainly intriguing, the study ultimately concluded that IRAK-M exerts an inhibitory effect under normal conditions by indirectly inducing inhibitory proteins (A20, SHIP-1, SOCS1 and IκB-α) [58]. Further clouding mechanistic insight, it has recently been revealed that the original Irak-m −/− mice commonly used to characterize this protein may actually contain a truncated version of IRAK-M [56]. Detailed sequencing analysis of the Irak-m gene product was conducted following TLR stimulation of BMDM from genotype confirmed Irak-m −/− mice [56].…”

Section: Transcription Inhibitionmentioning

confidence: 99%

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Modulating inflammation through the negative regulation of NF-κB signaling

Rothschild

McDaniel

Ringel‐Scaia

et al. 2018

Journal of Leukocyte Biology

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Immune system activation is essential to thwart the invasion of pathogens and respond appropriately to tissue damage. However, uncontrolled inflammation can result in extensive collateral damage underlying a diverse range of auto-inflammatory, hyper-inflammatory, and neoplastic diseases. The NF-κB signaling pathway lies at the heart of the immune system and functions as a master regulator of gene transcription. Thus, this signaling cascade is heavily targeted by mechanisms designed to attenuate overzealous inflammation and promote resolution. Mechanisms associated with the negative regulation of NF-κB signaling are currently under intense investigation and have yet to be fully elucidated. Here, we provide an overview of mechanisms that negatively regulate NF-κB signaling through either attenuation of signal transduction, inhibition of posttranscriptional signaling, or interference with posttranslational modifications of key pathway components. While the regulators discussed for each group are far from comprehensive, they exemplify common mechanistic approaches that inhibit this critical biochemical signaling cascade. Despite their diversity, a commonality among these regulators is their selection of specific targets at key inflection points in the pathway, such as TNF-receptor-associated factor family members or essential kinases. A better understanding of these negative regulatory mechanisms will be essential to gain greater insight related to the maintenance of immune system homeostasis and inflammation resolution. These processes are vital elements of disease pathology and have important implications for targeted therapeutic strategies.

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Section: Transcription Inhibitionsupporting

confidence: 82%

Section: Transcription Inhibitionmentioning

confidence: 99%

Section: Transcription Inhibitionmentioning

confidence: 99%

See 1 more Smart Citation

Modulating inflammation through the negative regulation of NF-κB signaling

Rothschild

McDaniel

Ringel‐Scaia

et al. 2018

Journal of Leukocyte Biology

Self Cite

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“…TLR and WNT activation in tumor cells drive IRAK-M expression, which promotes tumorigenesis by preventing STAT3 proteasomal degradation (25). Another study confirmed the protective role of IRAK-M against AOM/DSS-induced tumorigenesis, although the authors reported resistance to DSS colitis and attenuation of intestinal microbial translocation in Irak-m -/- mice(26). …”

Section: Innate Sensors and Immune Signalingmentioning

confidence: 86%

“…IRAK-M is a negative regulator of TLR/NK-κB signaling and found to be upregulated in IBD and CRC patients (25, 26). Irak-m -/- mice showed enhanced colitis but reduced tumorigenesis following AOM/DSS treatment (25).…”

Section: Innate Sensors and Immune Signalingmentioning

confidence: 99%

Novel insights into microbiome in colitis and colorectal cancer

Yang¹,

Jobin

2017

Current Opinion in Gastroenterology

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Purpose of review Microbiota is a major component of the etiology of inflammatory bowel diseases (IBD) and colorectal cancer (CRC). Here, we summarize key advances achieved the past 18 months (ending June 2017) toward a better understanding of the role of microbiota in colitis and CRC development. Recent findings Accumulating evidence shows the essential role of intestinal barrier function (e.g., mucus, IgA, LCN2, LYPD8) in protecting against bacteria-induced inflammation and tumor development. Numerous signaling pathways (e.g., TLRs, NLRs), metabolites (e.g., indole, bile acids, retinoic acid) and small non-coding RNAs (e.g., miRNA) have been identified as key mediators regulating host-microbe interactions in the intestine. Novel microbial drivers of colitis and tumorigenesis (e.g., Alistipes finegoldii, Atopobium parvalum, Peptostreptococcus anaerobius) have been identified and their disease-promoting activities have been described. Summary IBD-associated colorectal cancer results from a complex breakdown of communication between the host and its microbiota, involving barrier function, immune signaling and metabolites.

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IRAK-M Plays A Role in the Pathology of Amyotrophic Lateral Sclerosis Through Suppressing the Activation of Microglia

Zhong,

Li,

et al. 2024

Mol Neurobiol

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BackgroundMicroglial activation plays a crucial role in the disease progression in amyotrophic lateral sclerosis (ALS). Interleukin receptor-associated kinases-M (IRAK-M) is an important negative regulatory factor in the Tolllike receptor 4 (TLR4) pathway during microglia activation, and its mechanism in this process is still unclear. In the present study, we aimed to investigate the dynamic changes of IRAK-M and its protective effects for motor neuron in SOD1-G93A mouse model of ALS. Methods qPCR(Real-time Quantitative PCR Detecting System) were used to examine the mRNA levels of IRAK-M in the spinal cord in both SOD1-G93A mice and their age-matched wild type (WT) littermates at 100 and 140 days of age. we established an adeno-associated virus 9 (AAV9)-based platform by which IRAK-M was targeted mostly to microglial cells to investigate whether this approach could provide a protection in the SOD1-G93A mouse . ResultsCompared with age-matched WT mice, IRAK-M mRNA level was elevated at 100 and 140 days in the anterior horn region of spinal cords in the SOD1-G93A mouse. AAV9-IRAK-M treated SOD1-G93A mice showed reduction of IL-1β mRNA levels and signi cant improvements in the numbers of spinal motor neurons in spinal cord. Mice also showed previously reduction of muscle atrophy. ConclusionsOur data revealed the dynamic changes of IRAK-M during ALS pathological progression and demonstrated that an AAV9-IRAK-M deliverywas an effective and translatable therapeutic approach for ALS. These ndings may help identify potential molecular targets for ALS therapy.

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Enhanced Mucosal Defense and Reduced Tumor Burden in Mice with the Compromised Negative Regulator IRAK-M

Cited by 20 publications

References 46 publications

Modulating inflammation through the negative regulation of NF-κB signaling

Modulating inflammation through the negative regulation of NF-κB signaling

Novel insights into microbiome in colitis and colorectal cancer

IRAK-M Plays A Role in the Pathology of Amyotrophic Lateral Sclerosis Through Suppressing the Activation of Microglia

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