MD2 blockade prevents oxLDL-induced renal epithelial cell injury and protects against high-fat-diet-induced kidney dysfunction

Xu, Sujing; Luo, Wei; Xu, Xiaohong; Qian, Yuanyuan; Xu, Zheng; Wang, Yu; Shan, Xiaoou; Guan, Xiaofei; Lum, Hazel; Zhou, Huiping; Wang, Yi

doi:10.1016/j.jnutbio.2019.04.003

Cited by 17 publications

(20 citation statements)

References 17 publications

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“…MD2 has been well recognized as an indispensable accessory protein linking LPS and TLR4 [15,16], and targeting MD2 could effectively attenuate LPS-induced inflammatory response and sepsis [13,17,18]. Recently, we further prove that MD2 could also be an attractive therapeutic target for the treatment of many non-infectious chronic inflammatory diseases, including cardiac/kidney injuries induced by hypertension [19], obesity [20,21], and diabetes [22]. All these data suggest that MD2 can be a potential anti-inflammatory target in both acute and chronic diseases.…”

Section: Discussionmentioning

confidence: 94%

Selective targeting of the TLR4 co-receptor, MD2, prevents colon cancer growth and lung metastasis

Rajamanickam¹,

Yan²,

Xu³

et al. 2020

Int. J. Biol. Sci.

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Toll-like receptor (TLR) signaling is an emerging pathway in tumor cell invasion and metastasis. Myeloid differentiation protein-2 (MD2) contributes to ligand recognition and activation of TLRs in response to exogenous microbial insults or endogenous agents. We hypothesized that blocking MD2 using a specific inhibitor would prevent TLR4-mediated inflammatory responses and metastatic cancer growth. Here, we report that a MD2 inhibitor, L6H21, inhibited migration and invasion of LPS-activated colon cancer CT26.WT cells. These activities were accompanied by inhibition of nuclear factor-κB (NF-κB) activation, and thereby inhibition of the production of pro-inflammatory cytokines and adhesive molecules in colon cancer cells. Furthermore, L6H21 inhibited CT26.WT metastasis to the lung in BALB/c mice as well as suppressed colitis-induced colon cancer induced by azoxymethane/dextran sulfate sodium (AOM/DSS). Taken together, our results demonstrated that L6H21 suppressed tumor invasion and metastasis through blocking TLR4-MD2/NF-κB signaling axis. These findings reveal that inhibition of MD2 may be an important target for the development of colon cancer therapies.

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Section: Discussionmentioning

confidence: 94%

Selective targeting of the TLR4 co-receptor, MD2, prevents colon cancer growth and lung metastasis

Rajamanickam¹,

Yan²,

Xu³

et al. 2020

Int. J. Biol. Sci.

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“…Considering all of these variables, it is plausible that MD2 acts as a scavenger co-receptor and interacts with various modified/altered proteins with different affinities. In support of this idea is our recent discovery that MD2 binds to saturated fatty acids and oxidized lipoproteins to initiate TLR4 signaling 23,25 . Future studies aimed at determining whether ligands with different affinities induce different intracellular signaling arms of TLR4 and when signaling thresholds are met will greatly enhance our understanding.…”

Section: Discussionmentioning

confidence: 91%

“…MD2 also mediates angiotensin II-induced cardiac inflammation through direct binding to Ang II 24 . We have also reported that oxidized lipoproteins activate TLR4 through MD2 in atherosclerotic lesions 25 . Although the role of MD2 in hyperglycemia-induced cardiac inflammatory injury is unknown, these evidences point to the intriguing possibility that glucose or glucose-derived factors interact with MD2 to activate TLR4.…”

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confidence: 76%

MD2 activation by direct AGE interaction drives inflammatory diabetic cardiomyopathy

et al. 2020

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Hyperglycemia activates toll-like receptor 4 (TLR4) to induce inflammation in diabetic cardiomyopathy (DCM). However, the mechanisms of TLR4 activation remain unclear. Here we examine the role of myeloid differentiation 2 (MD2), a co-receptor of TLR4, in high glucose (HG)-and diabetes-induced inflammatory cardiomyopathy. We show increased MD2 in heart tissues of diabetic mice and serum of human diabetic subjects. MD2 deficiency in mice inhibits TLR4 pathway activation, which correlates with reduced myocardial remodeling and improved cardiac function. Mechanistically, we show that HG induces extracellular advanced glycation end products (AGEs), which bind directly to MD2, leading to formation of AGEs-MD2-TLR4 complex and initiation of pro-inflammatory pathways. We further detect elevated AGE-MD2 complexes in heart tissues and serum of diabetic mice and human subjects with DCM. In summary, we uncover a new mechanism of HG-induced inflammatory responses and myocardial injury, in which AGE products directly bind MD2 to drive inflammatory DCM.

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“…In most models of murine obesity in which kidney abnormalities have been reported, animals have free access to high‐calorie foods, where fat represents 60% of the total caloric intake, which is known as a high‐fat diet (HFD) and the follow‐up fluctuates between 12 and 34 weeks (Borgeson et al, 2017; Cheng et al, 2019; Kim et al, 2019; Luo et al, 2019; Pereira et al, 2020; Saito et al, 2019; Szeto et al, 2016; Xu et al, 2019; Yamamoto et al, 2017). Although this strategy leads effectively to the establishment of obesity in rodents and is capable of reproducing many of the multi‐organ alterations known in humans, it doubles the typical proportion of fat ingestion in obese patients (Botchlett & Wu, 2018).…”

Section: Introductionmentioning

confidence: 99%

Early triggers of moderately high‐fat diet‐induced kidney damage

et al. 2021

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MD2 blockade prevents oxLDL-induced renal epithelial cell injury and protects against high-fat-diet-induced kidney dysfunction

Cited by 17 publications

References 17 publications

Selective targeting of the TLR4 co-receptor, MD2, prevents colon cancer growth and lung metastasis

Selective targeting of the TLR4 co-receptor, MD2, prevents colon cancer growth and lung metastasis

MD2 activation by direct AGE interaction drives inflammatory diabetic cardiomyopathy

Early triggers of moderately high‐fat diet‐induced kidney damage

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