Impaired Inflammatory Response to LPS in Type 2 Diabetes Mellitus

Khondkaryan, Lusine; Margaryan, Sona; Poghosyan, David; Manukyan, Gayane

doi:10.1155/2018/2157434

Cited by 27 publications

(26 citation statements)

References 47 publications

(42 reference statements)

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“…DAVID analyses do not take into consideration the direction of change in gene expression, but significantly enriched gene ontology terms from BM-derived and wound-derived Gr-1 þ cells also showed overlap of a number of terms ( Supplementary Table S1, highlighted in yellow) relating to leukocyte activation. This is consistent with previous reports showing aberrant activation (both hyper-and hyporesponsiveness) in a variety of myeloid cell subsets in diabetic patients and animal models (Bannon et al, 2013;Khondkaryan et al, 2018;Miao et al, 2012;Mirza and Koh, 2011;Satoh et al, 2010).…”

Section: Gene Expression Profiling Of Bm-derived and Wound-derived Grsupporting

confidence: 93%

“…A more recent study in mice showed that genetic ablation of myeloid cells impaired wound healing, which again was associated with increased accumulation of neutrophils (Lucas et al, 2010;Mirza et al, 2009). Recent studies in human patients with diabetes showed an association with increased inflammatory cytokines in the circulation and a failure of myeloid cells isolated from these patients to respond to further stimulation (Khondkaryan et al, 2018). Altogether these studies and the data presented here support the idea that the diabetic environment induces a highly proinflammatory phenotype in myeloid cells during differentiation in the BM, inducing a tolerance-like phenotype, which upon challenge results in a reduced response, leading to a chronic inflammatory phenotype and impaired wound healing.…”

Section: Discussionmentioning

confidence: 99%

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Chronic Inflammation in Response to Injury: Retention of Myeloid Cells in Injured Tissue Is Driven by Myeloid Cell Intrinsic Factors

Torbica

Wicks

Umehara

et al. 2019

Journal of Investigative Dermatology

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Chronic inflammation is a hallmark of impaired healing in a plethora of tissues, including skin, and is associated with aging and diseases such as diabetes. Diabetic chronic skin wounds are characterized by excessive myeloid cells that display an aberrant phenotype, partially mediated by stable intrinsic changes induced during hematopoietic development. However, the relative contribution of myeloid celleintrinsic factors to chronic inflammation versus aberrant signals from the local environmental was unknown. Moreover, identification of myeloid cell intrinsic factors that contribute to chronic inflammation in diabetic wounds remained elusive. Here we show that Gr-1 þ CD11b þ myeloid cells are retained specifically within the presumptive granulation tissue region of the wound at a higher density in diabetic mice and associate with endothelial cells at the site of injury with a higher frequency than in nondiabetic mice. Adoptive transfer of myeloid cells demonstrated that aberrant wound retention is due to myeloid cell intrinsic factors and not the local environment. RNA sequencing of bone marrow and wound-derived myeloid cells identified Selplg as a myeloid cell intrinsic factor that is deregulated in chronic wounds. In vivo blockade of this protein significantly accelerated wound healing in diabetic mice and may be a potential therapeutic target in chronic wounds and other chronic inflammatory diseases.

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Section: Gene Expression Profiling Of Bm-derived and Wound-derived Grsupporting

confidence: 93%

Section: Discussionmentioning

confidence: 99%

Chronic Inflammation in Response to Injury: Retention of Myeloid Cells in Injured Tissue Is Driven by Myeloid Cell Intrinsic Factors

Torbica

Wicks

Umehara

et al. 2019

Journal of Investigative Dermatology

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“…Our results further demonstrated the increased expression of the inflammatory cytokines in db/db mice. One of the main triggers of inflammation in diabetes is the gut microbiota, such as LPS [30]. LPS is the inflammatory component of the cell wall of the gram-negative bacteria.…”

Section: Discussionmentioning

confidence: 99%

Ubiquitin fold modifier 1 activates NF-κB pathway by down-regulating LZAP expression in the macrophage of diabetic mouse model

Zhang

Shi

et al. 2020

Bioscience Reports

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Inflammatory response is closely related with the development of many serious health problems worldwide including diabetes mellitus (DM). Ubiquitin-fold modifer 1 (Ufm1) is a newly discovered ubiquitin-like protein, while its function remains poorly investigated, especially in inflammatory response and DM. In the present study, we analyzed the role of Ufm1 on inflammatory response in DM, and found that the proinflammatory cytokine levels (tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6) and IL-1β) and Ufm1 expression were highly increased both in the peritoneal macrophages of db/db mice and Raw264.7 cells induced by lipopolysaccharide (LPS). Western blot and luciferase reporter assay showed that NF-κB pathway was obviously activated in macrophages and the expression of LZAP, an inhibitor of NF-κB pathway, was down-regulated. With the LZAP knockdown plasmid and activation plasmid, we demonstrated that NF-κB/p65 activation was inhibited by LZAP in macrophages. The interaction of Ufm1 and LZAP was further proved with co-immunoprecipitation assay in HEK293 and Raw264.7 cells. The LZAP expression was also related with the presence of Ufm1 demonstrated by Ufm1 knockdown plasmid and activation plasmid. Besides that, we finally proved that the expression and activation of Ufm1 induced by LPS were regulated by JNK/ATF2 and JNK/c-Jun pathway with the use of SP600125. In conclusion, the present study demonstrated that Ufm 1 could activate NF-κB pathway by down-regulating LZAP in macrophage of diabetes, and its expression and activation were regulated by JNK/ATF2 and c-Jun pathway.

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“…The expression of TLR2 and TLR4 further declines in diabetes patients with pneumonia. 26,27 Monocytes and macrophages can directly phagocytose pathogens. The phagocytic and killing capability of alveolar macrophages from diabetic mice decreased.…”

Section: Dovepressmentioning

confidence: 99%

<p>The Effects of Type 2 Diabetes and Postoperative Pneumonia on the Mortality in Inpatients with Surgery</p>

Liu

et al. 2019

DMSO

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The aim of the study was to explore the relationship between type 2 diabetes (T2DM) and postoperative pneumonia, and the effects of T2DM and postoperative pneumonia on the mortality in inpatients with surgery. Methods: A retrospective study was conducted on 43,174 inpatients with surgery in The First Hospital of Qinhuangdao. These patients were divided into four groups according to T2DM and postoperative pneumonia, Group A subjects without T2DM and postoperative pneumonia, Group B subjects with T2DM only, Group C subjects with postoperative pneumonia only and Group D subjects with T2DM and postoperative pneumonia. Inhospital mortality was collected. Results: The incidences of postoperative pneumonia were higher in patients with T2DM than patients without T2DM (T2DM 3.2% vs Non-diabetes 1.7%, χ 2 =36.219, P<0.001). The mortalities were 0.3% in Group A, 0.3% in Group B, 4.6% in Group C and 8.6% in Group D. In multiple logistic regression analysis, adjusted for sex, age, emergency admissions, coronary heart disease, heart failure, chronic kidney disease, hypoproteinemia, stroke and transient ischemic attack, the mortalities of Group C and Group D were 4.515 (95% CI: 2.779～7.336, P<0.001) times and 8.468 (95% CI: 3.567～20.099, P<0.001) times than the mortality of Group A. Conclusion: T2DM is susceptible to postoperative pneumonia. The mortality increased in patients with postoperative pneumonia. When patients with T2DM and postoperative pneumonia at the same time, the mortality increased further. In T2DM patients with postoperative pneumonia, perioperative management should be improved for patient safety.

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Impaired Inflammatory Response to LPS in Type 2 Diabetes Mellitus

Cited by 27 publications

References 47 publications

Chronic Inflammation in Response to Injury: Retention of Myeloid Cells in Injured Tissue Is Driven by Myeloid Cell Intrinsic Factors

Chronic Inflammation in Response to Injury: Retention of Myeloid Cells in Injured Tissue Is Driven by Myeloid Cell Intrinsic Factors

Ubiquitin fold modifier 1 activates NF-κB pathway by down-regulating LZAP expression in the macrophage of diabetic mouse model

<p>The Effects of Type 2 Diabetes and Postoperative Pneumonia on the Mortality in Inpatients with Surgery</p>

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