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Clausen, Björn E.; Burkhardt, C.; Reith, Walter; Renkawitz, Rainer; Förster, Irmgard

doi:10.1023/a:1008942828960

Cited by 1,877 publications

(1,098 citation statements)

References 46 publications

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“…Myeloid cells that play dominant roles in the development of obesity-induced diabetes appear to be Mfs as was shown in the current in vitro investigation. However, the role of other myeloid cells such as dendritic cells or granulocytes that are target cells of Cre-mediated gene deletion in Atg7 cKO mice 49 cannot be totally eliminated, as both granulocytes and dendritic cells participate in the insulin resistance associated with obesity. 50,51 The development of T2D in Atg7 cKO-ob/ob mice but not in lean Atg7 cKO mice suggests that autophagy-deficient myeloid cells do not display significant inflammatory phenotypes in the basal state, but show proinflammatory features in the presence of activators of inflammation or metabolic stress.…”

Section: Discussionmentioning

confidence: 99%

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Autophagy deficiency in myeloid cells increases susceptibility to obesity-induced diabetes and experimental colitis

et al. 2016

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(2016) Autophagy deficiency in myeloid cells increases susceptibility to obesity-induced diabetes and experimental colitis, Autophagy, 12:8, 1390-1403, DOI: 10.1080/15548627.2016 ABSTRACT Autophagy, which is critical for the proper turnover of organelles such as endoplasmic reticulum and mitochondria, affects diverse aspects of metabolism, and its dysregulation has been incriminated in various metabolic disorders. However, the role of autophagy of myeloid cells in adipose tissue inflammation and type 2 diabetes has not been addressed. We produced mice with myeloid cell-specific deletion of Atg7 (autophagy-related 7), an essential autophagy gene (Atg7 conditional knockout [cKO] mice). While Atg7 cKO mice were metabolically indistinguishable from control mice, they developed diabetes when bred to ob/w mice (Atg7 cKO-ob/ob mice), accompanied by increases in the crown-like structure, inflammatory cytokine expression and inflammasome activation in adipose tissue. Mfs (macrophages) from Atg7 cKO mice showed significantly higher interleukin 1 b release and inflammasome activation in response to a palmitic acid plus lipopolysaccharide combination. Moreover, a decrease in the NAD C :NADH ratio and increase in intracellular ROS content after treatment with palmitic acid in combination with lipopolysaccharide were more pronounced in Mfs from Atg7 cKO mice, suggesting that mitochondrial dysfunction in autophagy-deficient Mfs leads to an increase in lipid-induced inflammasome and metabolic deterioration in Atg7 cKO-ob/ob mice. Atg7 cKO mice were more susceptible to experimental colitis, accompanied by increased colonic cytokine expression, T helper 1 skewing and systemic bacterial invasion. These results suggest that autophagy of Mfs is important for the control of inflammasome activation in response to metabolic or extrinsic stress, and autophagy deficiency in Mfs may contribute to the progression of metabolic syndrome associated with lipid injury and colitis.

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Section: Discussionmentioning

confidence: 99%

“…49 Cre-mediated deletion of Atg7 was confirmed by PCR using genomic DNA from peritoneal Mfs and primers flanking the floxed region as previously reported. 14 Atg7 cKO-ob/ob mice were generated by crossing Atg7 cKO mice to ob/w (heterozygous Lep knockout) mice twice.…”

Section: Micementioning

confidence: 99%

Autophagy deficiency in myeloid cells increases susceptibility to obesity-induced diabetes and experimental colitis

et al. 2016

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“…For animals, 8-week-old female C57BL/6 mice were purchased from the Vital River Laboratories (Beijing, China), and FPN1-floxed and LysM-Cre mice with the 129/SvEvTac background were provided by Dr. Fudi Wang [6,[26][27][28]. LysM-Cre mice were mated with FPN1 flox/flox mice to create the strain in which FPN was inactivated in macrophages.…”

Section: Animal Experimentsmentioning

confidence: 99%

Estrogen contributes to regulating iron metabolism through governing ferroportin signaling via an estrogen response element

Qian

Yin

Chen

et al. 2015

Cellular Signalling

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Ferroportin (FPN) is the only known iron exporter in mammalian cells, and is universally expressed in most types of cells. FPN signaling plays a crucial role in maintaining iron homeostasis through governing the level of intracellular iron. Serum iron storage is conversely related with the estrogen level in the female bodies, and women in post-menopause are possibly subjected to iron retention. However, the potential effects of estrogen on iron metabolism are not clearly understood. Here, FPN mRNA transcription in all selected estrogen receptor positive (ER+) cells was significantly reduced upon 17β-estradiol (E2) treatment; and this inhibitory effect could be attenuated by ER antagonist tamoxifen. Likewise, in murine bone marrow-derived macrophages (BMDMs), FPN reduction with elevated intracellular iron (reflected by increased ferritin) was observed in response to E2; however, ferritin level barely responded to E2 in FPN-null BMDMs. The observation of inhibition of FPN mRNA expression was not replicated in ER − cells upon E2. A functional estrogen response element (ERE) was identified within the promoter of FPN, and this ERE was responsible for the suppressive effect of E2 on FPN expression. Moreover, ovariectomized (OVX) and sham-operated (SHAM) mice were used to further confirm the in vitro finding. The expression of hepatic FPN was induced in OVX mice, compared to that in the SHAM mice. Taken together, our results demonstrated that estrogen is involved in regulating FPN expression through a functional ERE on its promoter, providing additional insights into a vital role of estrogen in iron metabolism.

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“…16 Crossing Myd88 LSL/LSL mice with pvillin-Cre 17 mice and LysM-Cre mice 18 lead to excision of the intron-gene-trap and therefore re-expression of Myd88 on mRNA and protein level (Fig. 1C) in intestinal epithelial ( Myd88 IEC ) or myeloid cells (bone marrow derived macrophages, Myd88 MYEL ; for a schematic representation of the mouse strains refer to Supplementary Fig.…”

Section: Resultsmentioning

confidence: 99%

Cell-type specific MyD88 signaling is required for intestinal tumor initiation and progression to malignancy

Holtorf

Conrad²,

Holzmann³

et al. 2018

OncoImmunology

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The signal adapter MyD88, an essential component of Toll-like receptor (TLR) signaling, is important for gut-microbiome interactions. However, its contribution to cancer and its cell-type specific functions are controversially discussed. Therefore, we generated new tissue-specific mouse models and analyzed the clinical importance in human colorectal cancer. A gene-trap was inserted into the murine Myd88 gene (Myd88LSL), yielding MyD88-deficient background with Cre-mediated re-expression in myeloid (MYEL) or intestinal epithelial cells (IECs). These lines were bred with the Apc1638N model that develops invasive adenocarcinoma and analyzed at 12 months. Further, two patient collectives of colorectal cancer (n = 61, and n = 633) were analyzed for expression of Myd88 and TLRs. MyD88 expression was significantly increased in carcinomas, and increased intratumoral levels of MyD88 and TLR pathway components were associated with significantly shorter disease-free (P = .011), and overall survival (P < .0001). In accordance, fully MyD88-deficient mice showed highly significantly decreased tumor incidence, tumor numbers, increased survival, and, importantly, fully lacked malignant lesions. Thus, MyD88 is essential for tumorigenesis and especially progression to malignancy. Tissue-specific re-expression of MyD88 highly significantly increased tumor initiation by differing mechanisms. In intestinal epithelia, MyD88 enhanced epithelial turnover, whereas in myeloid cells, it led to increased production of tumor- and stemness-enhancing cytokines, significantly associated with altered expression of adaptive immune genes. However, neither re-expression of MyD88 in IECs or myeloid cells was sufficient for malignant progression to carcinoma. Thus, MyD88 crucially contributes to colorectal cancer initiation and progression with non-redundant and cell-type specific functions, constituting an attractive therapeutic target.

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Untitled

Cited by 1,877 publications

References 46 publications

Autophagy deficiency in myeloid cells increases susceptibility to obesity-induced diabetes and experimental colitis

Autophagy deficiency in myeloid cells increases susceptibility to obesity-induced diabetes and experimental colitis

Estrogen contributes to regulating iron metabolism through governing ferroportin signaling via an estrogen response element

Cell-type specific MyD88 signaling is required for intestinal tumor initiation and progression to malignancy

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