IL-1β-Mediated Innate Immunity Is Amplified in the <i>db/db</i> Mouse Model of Type 2 Diabetes

O’Connor, Jason C.; Satpathy, Ansuman T.; Hartman, Matthew E.; Horvath, E; Kelley, Keith W.; Dantzer, Robert; Johnson, Rodney W.; Freund, Gregory G.

doi:10.4049/jimmunol.174.8.4991

Cited by 78 publications

(82 citation statements)

References 49 publications

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“…The injection of LPS into db/db mice induced production of IL1β in macrophages, and evidence of innate-immunity associated illness was greater in db/db mice compared to db/+ mice 106 . These effects could be blocked by administration of an IL1R antagonist 106 .…”

Section: [H3] Nlrp3-il1 Pathwaymentioning

confidence: 93%

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Innate immunity in diabetes and diabetic nephropathy

2015

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Abstract:The innate immune system consists of several classes of pattern recognition receptors (PRRs), including membrane-bound Toll-like receptors (TLRs) and nucleotide-binding domain leucine-rich oligomerization domain (NOD)-like receptors (NLRs).These receptors detect pathogen-associated molecular patterns (PAMPs) and danger-associated molecular patterns (DAMPs) in the extracellular and intracellular space. Intracellular NLRs constitute inflammasomes, which activate and release caspase-1, IL1β, and IL18 and thus initiate an inflammatory response. Systemic and local low-grade inflammation and release of proinflammatory cytokines are implicated in the development and progression of diabetes mellitus and diabetic nephropathy. TLR2, TLR4, and the NLRP3 inflammasome are critically involved in the inflammatory responses in pancreatic islets, adipose, liver and kidney tissues. This Review discusses how innate immune system-driven inflammatory processes can lead to apoptosis, tissue fibrosis, and organ dysfunction to cause insulin resistance, impaired insulin secretion, and renal failure. We propose that careful targeting of TLR2, TLR4, and NLRP3 signalling pathways may be beneficial for the treatment of diabetes mellitus and diabetic nephropathy. 2 Key points The innate immune system consists of several classes of pattern recognition receptors, including TLRs and NLRs, which detect pathogen-associated and danger-associated molecular patterns and initiate an inflammatory response  TLR2 and TLR4 are the predominant toll-like receptors expressed on pancreatic β cells that trigger an inflammatory response in insulitis during type 1 diabetes mellitus  TLR2 and TLR4 signaling, and activation of NLRP3 inflammasomes results in production of various proinflammatory cytokines that can induce insulin resistance in type 2 diabetes mellitus (T2DM) and obesity  Innate immune responses in T2DM and obesity are modulated by the status of the gut microbiota, autophagy, and adipokines  TLR2, TLR4, NOD2, and NLRP3 inflammasome-mediated inflammation are involved in the perpetuation of inflammation in diabetic nephropathy  The activation of TLRs and NLRs stimulates the expression of MCP-1, which is associated with the progression of diabetic nephropathy [H1] IntroductionThe prevalence of diabetes mellitus is estimated to be 8.3%, affecting ~387 million people as of 2014. The number of patients living with diabetes mellitus is expected to increase to ~592 million by 2035, as reported by the International Diabetes Federation 1 . The incidence of end-stage renal disease (ESRD) is also rapidly increasing worldwide but varies up to 15-fold by country. In 2012, the number of new diagnoses of ESRD worldwide ranged from 25 to 467 patients per million. The proportion of new cases of ESRD with diabetes mellitus as the primary cause also differs by country, with 66% cases reported in Singapore and 12-16% cases reported in Ukraine, Romania, and the Netherlands 2 . Although intensified multifactorial intervention in patients with type 2 diabete...

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Section: [H3] Nlrp3-il1 Pathwaymentioning

confidence: 93%

“…These effects could be blocked by administration of an IL1R antagonist 106 . The activation of NLRP3 has an important role in the production of IL1 in T2DM and it may be an important target for disease treatment 107,108 .…”

Section: [H3] Nlrp3-il1 Pathwaymentioning

confidence: 99%

Innate immunity in diabetes and diabetic nephropathy

2015

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“…Blood was collected from the lateral saphenous vein as we described previously (6). Briefly, blood glucose levels were measured using a One Touch Ultra glucometer (Johnson & Johnson) per the manufacturer's instructions.…”

Section: Blood Glucose Measurementmentioning

confidence: 99%

“…TNF-␣ was measured by ELISA as we have described previously (6). Briefly, polyclonal anti-mouse TNF-␣ Ab at 2 g/ml was absorbed to 96-well microtiter plates overnight at 25°C.…”

Section: Tnf-␣mentioning

confidence: 99%

“…We have recently shown in a mouse model of T2D that diabetic mice have excessive responsivity to LPS demonstrating heightened up-regulation of IL-1␤ and failure to appropriately increases the IL-1 counterregulator molecules IL-1R antagonist (IL-1RA) and IL-1R 2. The consequence of this dysregulation of the IL-1␤ pathway is increased and prolonged sickness behavior in response to LPS (6). In macrophages, LPS causes elaboration of TNF-␣ and TNF-␣ is critical to the brain-based immunobehavioral consequences of bacterialrelated illness (7).…”

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Augmented Lipopolysaccharide-Induced TNF-α Production by Peritoneal Macrophages in Type 2 Diabetic Mice Is Dependent on Elevated Glucose and Requires p38 MAPK

Sherry¹,

O’Connor²,

Kramer

et al. 2007

The Journal of Immunology

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Dysregulated inflammation is a complication of type 2 diabetes (T2D). In this study, we show that augmented LPS-induced TNF-α production by resident peritoneal macrophages (PerMφ) in type 2 diabetic (db/db) mice is dependent on elevated glucose and requires p38 MAPK. Intraperitoneal LPS administered to db/db and nondiabetic (db/+) mice induced 3- and 4-fold more TNF-α in the peritoneum and serum, respectively, of db/db mice as compared with db/+ mice. Examination of the TLR-4/MD2 complex and CD14 expression showed no difference between db/db and db/+ PerMφ. Ex vivo stimulation of PerMφ with LPS produced a similar 3-fold increase in TNF-α production in db/db PerMφ when compared with db/+ PerMφ. PerMφ isolated from db/+ mice incubated in high glucose (4 g/L) medium for 12 h produced nearly 2-fold more TNF-α in response to LPS than PerMφ incubated in normal glucose medium (1 g/L). LPS-dependent stimulation of PI3K activity, ERK1/2 activation, and p38 kinase activity was greater in PerMφ from db/db mice as compared with db/+ mice. Only inhibition of p38 kinase blocked LPS-induced TNF-α production in PerMφ from db/db mice. Taken together, these data indicate that augmented TNF-α production induced by LPS in macrophages during diabetes is due to hyperglycemia and increased LPS-dependent activation of p38 kinase.

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Peripheral Inflammation and Demyelinating Diseases

Murta

Ferrari

2016

Advances in Experimental Medicine and Biology

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In recent decades, several neurodegenerative diseases have been shown to be exacerbated by systemic inflammatory processes. There is a wide range of literature that demonstrates a clear but complex relationship between the central nervous system (CNS) and the immunological system, both under naïve or pathological conditions. In diseased brains, peripheral inflammation can transform "primed" microglia into an "active" state, which can trigger stronger pathological responses. Demyelinating diseases are a group of neurodegenerative diseases characterized by inflammatory lesions associated with demyelination, which in turn induces axonal damage, neurodegeneration, and progressive loss of function. Among them, the most important are multiple sclerosis (MS) and neuromyelitis optica (NMO). In this review, we will analyze the effect of specific peripheral inflammatory stimuli in the progression of demyelinating diseases and discuss their animal models. In most cases, peripheral immune stimuli are exacerbating.

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IL-1β-Mediated Innate Immunity Is Amplified in the db/db Mouse Model of Type 2 Diabetes

Cited by 78 publications

References 49 publications

Innate immunity in diabetes and diabetic nephropathy

Innate immunity in diabetes and diabetic nephropathy

Augmented Lipopolysaccharide-Induced TNF-α Production by Peritoneal Macrophages in Type 2 Diabetic Mice Is Dependent on Elevated Glucose and Requires p38 MAPK

Peripheral Inflammation and Demyelinating Diseases

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