Inflammation is More Persistent in Type 1 Diabetic Mice

Graves, Dana T.; Naguib, Ghada Hussein; Lü, Huafei; Leone, Cataldo; Hsue, H.; Krall, Elizabeth A.

doi:10.1177/154405910508400406

Cited by 69 publications

(71 citation statements)

References 28 publications

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“…We found here that the local periodontal inflammatory response in diabetic animals was greater, as evidenced by an enhanced expression of TNF-␣ and a larger PMN infiltrate, and this finding is consistent with findings in other models (15,33). These local findings were in agreement Ϫ cells per total number of CD18 Ϫ cells were counted.…”

Section: Discussionsupporting

confidence: 92%

Aggregatibacter actinomycetemcomitans Infection Enhances Apoptosis In Vivo through a Caspase-3-Dependent Mechanism in Experimental Periodontitis

et al. 2012

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ABSTRACTThe purpose of this study was to test the hypothesis that diabetes aggravates periodontal destruction induced byAggregatibacter actinomycetemcomitansinfection. Thirty-eight diabetic and 33 normal rats were inoculated withA. actinomycetemcomitansand euthanized at baseline and at 4, 5, and 6 weeks after inoculation. Bone loss and the infiltration of polymorphonuclear leukocytes (PMNs) in gingival epithelium were measured in hematoxylin-eosin-stained sections. The induction of tumor necrosis factor alpha (TNF-α) was evaluated by immunohistochemistry and of apoptotic cells by a TUNEL (terminal deoxynucleotidyltransferase-mediated dUTP-biotin nick end labeling) assay. AfterA. actinomycetemcomitansinfection, the bone loss in diabetic rats was 1.7-fold and the PMN infiltration 1.6-fold higher than in normoglycemic rats (P< 0.05). The induction of TNF-α was 1.5-fold higher and of apoptotic cells was up to 3-fold higher in diabetic versus normoglycemic rats (P< 0.05). Treatment with a caspase-3 inhibitor significantly blocked noninflammatory cell apoptosis induced byA. actinomycetemcomitansinfection in gingival epithelium and connective tissue (P< 0.05). These results provide new insight into how diabetes aggravatesA. actinomycetemcomitans-induced periodontal destruction in rats by significantly increasing the inflammatory response, leading to increased bone loss and enhancing apoptosis of gingival epithelial and connective tissue cells through a caspase-3-dependent mechanism. Antibiotics had a more pronounced effect on many of these parameters in diabetic than in normoglycemic rats, suggesting a deficiency in the capacity of diabetic animals to resist infection.

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Section: Discussionsupporting

confidence: 92%

Aggregatibacter actinomycetemcomitans Infection Enhances Apoptosis In Vivo through a Caspase-3-Dependent Mechanism in Experimental Periodontitis

et al. 2012

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“…C57BL/6J and TLR2 knockout (TLR2-/-) mice were obtained from Jackson Laboratories and fed a high-fat diet for 16 weeks as described previously (3). Mice infection with P. gingivalis was conducted by using mouse calvaria model (27).…”

Section: Methodsmentioning

confidence: 99%

“…To determine whether impaired bacterial clearance in DIO mice (3) is associated with dysregulated NO production upon infection with P. gingivalis, we analyzed the expression of iNOS-in infected tissue from lean mice and from mice with DIO, using an in vivo murine calvarial model (27). iNOS expression was dramatically attenuated in DIO mice at day 3 after infection in comparison with lean mice (Fig.…”

Section: Dio Blunts P Gingivalis-induced Inos Expressionmentioning

confidence: 99%

Signaling mechanisms involved in altered function of macrophages from diet-induced obese mice affect immune responses

Zhou

Leeman

Amar

2009

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

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Recent research links diet-induced obesity (DIO) with impaired immunity, although the underlying mechanisms remain unclear. We find that the induction of inducible NO synthase (iNOS) and cytokines is suppressed in mice with DIO and in bone marrow macrophages (BMM⌽) from mice with DIO exposed to an oral pathogen, Porphyromonas gingivalis. BMM⌽ from lean mice pretreated with free fatty acids (FFAs) and exposed to P. gingivalis also exhibit a diminished induction of iNOS and cytokines. BMM⌽ from lean and obese mice exposed to P. gingivalis and analyzed by a phosphorylation protein array show a reduction of Akt only in BMM⌽ from mice with DIO. This reduction is responsible for diminished NF-B activation and diminished induction of iNOS and cytokines. We next observed that Toll-like receptor 2 (TLR2) is suppressed in BMM⌽ from DIO mice whereas carboxy-terminal modulator protein (CTMP), a known suppressor of Akt phosphorylation, is elevated. This elevation stems from defective TLR2 signaling. In BMM⌽ from lean mice, both FFAs and TNF-␣-via separate pathways-induce an increase in CMTP. However, in BMM⌽ from DIO mice, TLR2 can no longer inhibit the TNF-␣-induced increase in CTMP caused by P. gingivalis challenge. This defect can then be restored by transfecting WT TLR2 into BMM⌽ from DIO mice. Thus, feeding mice a high-fat diet over time elevates the CTMP intracellular pool, initially via FFAs activating TLR2 and later when the defective TLR2 is unable to inhibit TNF-␣-induced CTMP. These findings unveil a link between obesity and innate immunity.O besity has been found to lead to diminished immune response. Several epidemiological studies of obese individuals found evidence of increased susceptibility to infections, including postoperative infectious complications (1), and a positive correlation between body weight index and the incidence of nosocomial infections (2). Diet-induced obesity (DIO) interferes with the ability of the immune system to appropriately respond to Porphyromonas gingivalis infection (3) and causes a higher mortality rate in mice following infection with influenza virus (4).Obesity is known to elevate TNF-␣ levels in the plasma of obese subjects (5, 6). However, macrophage functions are impaired in obese animals, with reduced phagocytic capacity and a defective oxidative burst (7,8). The reduced cytokine expression in response to infection observed in obese mice has been linked to a dysfunction in macrophages and/or a defect in maturation of monocytes (3,4,9). Moreover, the ability of mature macrophages from an obese individual to elicit an antimicrobial and cytotoxic response may be inhibited (10). Macrophages sense the presence of microorganisms via pattern recognition receptors, especially members of the Tolllike receptor (TLR) family, and subsequently activate proinflammatory signal pathways. TLR2 is an important receptor by which macrophages recognize P. gingivalis (11)(12)(13)(14), and mediates destructive chronic inflammatory reactions or confers host protection against P. gingivalis in acut...

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“…A number of studies of animal models have highlighted the importance of TNF-a in possibly prolonging the immune response to plaque bacteria in both T1DM and T2DM and thereby promoting periodontitis in these conditions (Lalla et al 2000a,b, Graves et al 2004, Naguib et al 2004, Liu et al 2006a,b, Watanabe et al 2008, Pacios et al 2012. The role of TNF-a (and IL-6) in the enhanced immune responses to periodontal bacteria in diabetic mouse models has also been highlighted (Graves et al 2005, Nishihara et al 2009, Takano et al 2010). However, evidence for any association between levels of TNF-a in oral fluids or gingival tissues and T2DM in chronic periodontitis is inconsistent (Duarte et al 2007b, Navarro-Sanchez et al 2007, Ross et al 2010, Santos et al 2010b.…”

Section: Cytokines and Adipokinesmentioning

confidence: 99%

A review of the evidence for pathogenic mechanisms that may link periodontitis and diabetes

Taylor

Preshaw

Lalla

2013

Journal of Periodontology

217

258

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A review of the evidence for pathogenic mechanisms that may link periodontitis and diabetes Taylor JJ, Preshaw PM, Lalla E. A review of the evidence for pathogenic mechanisms that may link periodontitis and diabetes.Abstract Aims: To review the evidence for the molecular and cellular processes that may potentially link periodontal disease and diabetes. The pathogenic roles of cytokines and metabolic molecules (e.g. glucose, lipids) are explored and the role of periodontal bacteria is also addressed. Paradigms for bidirectional relationships between periodontitis and diabetes are discussed and opportunities for elaborating these models are considered. Methods: Database searches were performed using MeSH terms, keywords, and title words. Studies were evaluated and summarized in a narrative review. Results: Periodontal microbiota appears unaltered by diabetes and there is little evidence that it may influence glycaemic control. Small-scale clinical studies and experiments in animal models suggest that IL-1b, TNF-a, IL-6, OPG and RANKL may mediate periodontitis in diabetes. The AGE-RAGE axis is likely an important pathway of tissue destruction and impaired repair in diabetesassociated periodontitis. A role for locally activated pro-inflammatory factors in the periodontium, which subsequently impact on diabetes, remains speculative. Conclusion: There is substantial information on potential mechanistic pathways which support a close association between diabetes and periodontitis, but there is a real need for longitudinal clinical studies using larger patient groups, integrated with studies of animal models and cells/tissues in vitro.

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Inflammation is More Persistent in Type 1 Diabetic Mice

Cited by 69 publications

References 28 publications

Aggregatibacter actinomycetemcomitans Infection Enhances Apoptosis In Vivo through a Caspase-3-Dependent Mechanism in Experimental Periodontitis

Aggregatibacter actinomycetemcomitans Infection Enhances Apoptosis In Vivo through a Caspase-3-Dependent Mechanism in Experimental Periodontitis

Signaling mechanisms involved in altered function of macrophages from diet-induced obese mice affect immune responses

A review of the evidence for pathogenic mechanisms that may link periodontitis and diabetes

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