Increased Monocytic Activity and Biomarkers of Inflammation in Patients With Type 1 Diabetes

Devaraj, Sridevi; Glaser, Nicole; Griffen, Steve; Wang-Polagruto, Janice F.; Miguelino, Eric; Jialal, Ishwarlal

doi:10.2337/diabetes.55.03.06.db05-1417

Cited by 261 publications

(219 citation statements)

References 45 publications

Supporting

Mentioning

192

Contrasting

Unclassified

Order By: Relevance

“…Diabetes can be envisioned as a disease characterized by a chronic systemic inflammatory state disturbing the function of multiple vital body systems, in particular the vasculature (28,29). We hypothesized that hampered differentiation of EPC from myeloid progenitor cells in the BM might contribute significantly to the suboptimal endothelial repair under hyperglycemic conditions.…”

Section: Discussionmentioning

confidence: 99%

“…Given the proper differentiation factors, however, these BM precursor pools also give rise to important effector cells of the innate immune system such as macrophages (Mph) and dendritic cells (DC) (26,27), suggesting a common myeloid progenitor pool for EPC, Mph, granulocytes, monocytes, and DC. Because diabetes is increasingly being recognized to be a chronic systemic proinflammatory state (28,29), we hypothesized that the disturbed vascular repair in diabetes is related to an effect of hyperglycemia on the differentiation fate of myeloid BM precursors. We demonstrated that hyperglycemia indeed skews the BM potential from generating proangiogenic early EPC to the development of proinflammatory cells.…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Differentiation of Bone Marrow-Derived Endothelial Progenitor Cells Is Shifted into a Proinflammatory Phenotype by Hyperglycemia

Loomans

Haperen

Duijs

et al. 2009

Mol Med

View full text Add to dashboard Cite

Bone marrow (BM)-derived endothelial progenitor cells (EPC) contribute to vascular maintenance by participating in angiogenesis, re-endothelialization, and remodeling. Myeloid progenitor cells in the BM are functionally and quantitatively an important precursor pool for cells that contribute to these processes. However, these precursor pools in the BM also give rise to important effector cells of the innate immune system, such as macrophages and dendritic cells. We hypothesized that the disturbed repair responses that are being observed in diabetes mellitus are also related to an effect on functional and differentiation characteristics at the level of this bone marrow precursor pool. Indeed, we observed that bone marrow differentiation cultures for EPC, macrophages (Mph), or dendritic cells (DC) from hyperglycemic BM yielded 40% fewer EPC and 50% more Mph compared with control BM. These changes were directly related to the hemoglobin A 1C levels of the donor mice. BM-derived DC numbers were not affected by hyperglycemia. The composition of the BM was not altered; in particular, the numbers of CD31 + /Ly6C + cells, which serve as common progenitors for EPC, Mph, and DC, were unaffected. In addition, BM-derived EPC from hyperglycemic mice were less angiogenic and more proinflammatory in regards to endocytosis, T-cell activation, and interleukin 12 production. HMG-CoA (3-hydroxy-3-methylglutaryl coenzyme A) reductase inhibition by statin supplementation of the culture medium counteracted these hyperglycemia-induced changes. Our study results show that hyperglycemia alters the differentiation fate of BM precursor cells, reducing the potential to generate vascular regenerative cells and favoring the development of proinflammatory cells.

show abstract

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Differentiation of Bone Marrow-Derived Endothelial Progenitor Cells Is Shifted into a Proinflammatory Phenotype by Hyperglycemia

Loomans

Haperen

Duijs

et al. 2009

Mol Med

View full text Add to dashboard Cite

show abstract

“…Proinflammatory cytokines TNF-α, IL-6, and MCP-1 produced from M1 adipose tissue-resident macrophages contribute to insulin resistance [241]. Ly-6C hi monocytes are predominant in the blood of type 1 diabetic animals [247], and the monocytes isolated from patients with diabetes secrete higher levels of proinflammatory cytokines [248][249][250]. It is believed that the cytokines released from these cells influence peripheral inflammatory status.…”

Section: Diabetesmentioning

confidence: 99%

Microglia and Monocyte-Derived Macrophages in Stroke

2016

View full text Add to dashboard Cite

Historically, the brain has been considered an immune-privileged organ separated from the peripheral immune system by the blood-brain barrier. However, immune responses do occur in the brain in neurological conditions in which the integrity of the blood-brain barrier is compromised, exposing the brain to peripheral antigens and endogenous danger signals. While most of the associated pathological processes occur in the central nervous system, it is now clear that peripheral immune cells, especially mononuclear phagocytes, that infiltrate into the injury site play a key role in modulating the progression of primary brain injury development. As inflammation is a necessary and critical component for the subsequent injury resolution process, understanding the contribution of mononuclear phagocytes on the regulation of inflammatory responses may provide novel approaches for potential therapies. Furthermore, predisposed comorbid conditions at the time of stroke cause the alteration of stroke-induced immune and inflammatory responses and subsequently influence stroke outcome. In this review, we summarize a role for microglia and monocytes/macrophages in acute ischemic stroke in the context of normal and metabolically compromised conditions.

show abstract

“…However, metabolic disorders also appear to affect blood monocytes directly. A number of studies reported that monocytes both in patients with metabolic disorders and in dyslipidemic or diabetic mice undergo phenotypical and functional changes that may contribute directly to the development and progression of chronic inflammatory vascular diseases (8)(9)(10)(11)(12)(13).…”

mentioning

confidence: 99%

Redox regulation of MAPK phosphatase 1 controls monocyte migration and macrophage recruitment

Kim¹,

Ullevig

Zamora³

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

103

125

View full text Add to dashboard Cite

Monocytic adhesion and chemotaxis are regulated by MAPK pathways, which in turn are controlled by redox-sensitive MAPK phosphatases (MKPs). We recently reported that metabolic disorders prime monocytes for enhanced recruitment into vascular lesions by increasing monocytes' responsiveness to chemoattractants. However, the molecular details of this proatherogenic mechanism were not known. Here we show that monocyte priming results in the S-glutathionylation and subsequent inactivation and degradation of MKP-1. Chronic exposure of human THP-1 monocytes to diabetic conditions resulted in the loss of MKP-1 protein levels, the hyperactivation of ERK and p38 in response to monocyte chemoattractant protein-1 (MCP-1), and increased monocyte adhesion and chemotaxis. Knockdown of MKP-1 mimicked the priming effects of metabolic stress, whereas MKP-1 overexpression blunted both MAPK activation and monocyte adhesion and migration induced by MCP-1. Metabolic stress promoted the Sglutathionylation of MKP-1, targeting MKP-1 for proteasomal degradation. Preventing MKP-1 S-glutathionylation in metabolically stressed monocytes by overexpressing glutaredoxin 1 protected MKP-1 from degradation and normalized monocyte adhesion and chemotaxis in response to MCP-1. Blood monocytes isolated from diabetic mice showed a 55% reduction in MKP-1 activity compared with nondiabetic mice. Hematopoietic MKP-1 deficiency in atherosclerosis-prone mice mimicked monocyte priming and dysfunction associated with metabolic disorders, increased monocyte chemotaxis in vivo, and accelerated atherosclerotic lesion formation. In conclusion, we identified MKP-1 as a central redox-sensitive regulator of monocyte adhesion and migration and showed that the loss of MKP-1 activity is a critical step in monocyte priming and the metabolic stress-induced conversion of blood monocytes into a proatherogenic phenotype.M etabolic disorders such as obesity and diabetes are associated with a state of chronic, low-grade inflammation (1, 2), which appears to contribute to the development of micro-and macrovascular complications such as atherosclerosis, nephropathy, and retinopathy (3-5). The cellular and molecular mechanisms involved in chronic inflammation associated with metabolic disorders are not yet fully understood, but the recruitment of blood monocytes to sites of vascular injury appears to play a central and rate-limiting role in all these complications. Metabolic disorders impact blood vessels at multiple levels, including lipid depositions, endothelial injury, and smooth muscle cell proliferation and migration, which individually or in concert initiate monocyte recruitment and promote vascular inflammation (6, 7). However, metabolic disorders also appear to affect blood monocytes directly. A number of studies reported that monocytes both in patients with metabolic disorders and in dyslipidemic or diabetic mice undergo phenotypical and functional changes that may contribute directly to the development and progression of chronic inflammatory vascular diseases (8-13)...

show abstract

Increased Monocytic Activity and Biomarkers of Inflammation in Patients With Type 1 Diabetes

Cited by 261 publications

References 45 publications

Differentiation of Bone Marrow-Derived Endothelial Progenitor Cells Is Shifted into a Proinflammatory Phenotype by Hyperglycemia

Differentiation of Bone Marrow-Derived Endothelial Progenitor Cells Is Shifted into a Proinflammatory Phenotype by Hyperglycemia

Microglia and Monocyte-Derived Macrophages in Stroke

Redox regulation of MAPK phosphatase 1 controls monocyte migration and macrophage recruitment

Contact Info

Product

Resources

About