Toll-Like Receptors’ Pathway Disturbances are Associated with Increased Susceptibility to Infections in Humans

Frazão, Josias Brito; Errante, Paolo Ruggero; Condino‐Neto, Antônio

doi:10.1007/s00005-013-0243-0

Cited by 72 publications

(62 citation statements)

References 175 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…The TIR domain consists of three boxes of conserved residues set in a core sequence of 135-160 amino acids, which facilitate receptor-adaptor oligomerization 14 . The differential recruitment of these adaptor proteins results in the formation of a myddosome complex-an oligomeric signaling complex that consists of the adaptor proteins MyD88, IRAK1 and IRAK4-and activation of various signaling molecules, such as NFκB, MAPK, and interferon regulatory factor (IRF) and the subsequent production and release of various cytokines and chemokines ( Figure 1; Table 1) [15][16][17][18][19] .…”

Section: [H1] Prrs Of the Innate Immune System [H2] Toll-like Receptorsmentioning

confidence: 99%

Innate immunity in diabetes and diabetic nephropathy

2015

View full text Add to dashboard Cite

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...

show abstract

Section: [H1] Prrs Of the Innate Immune System [H2] Toll-like Receptorsmentioning

confidence: 99%

Innate immunity in diabetes and diabetic nephropathy

2015

View full text Add to dashboard Cite

show abstract

“…Our study showed a significant association between the presence of these two polymorphisms with a lower inflammatory grade in ESRD patients under HD. TLR4 is the primary receptor for lipopolysaccharide (LPS) from Gram-negative bacteria, but it also recognizes fungal mannan, parasitic phospholipids, viral envelop proteins and host heat shock proteins (12). The TLR4 polymorphism c.896A>G has been studied and it was related to an increased susceptibility to Gram-negative bacteremia and septic shock (16,17), by reducing LPS responsiveness.…”

Section: Discussionmentioning

confidence: 99%

“…TLR targeted drugs have been approved and small-molecule compounds are being investigated in the treatment of viral infections (29). However, therapeutic modulation by TLRs could cause unexpected unsafe responses that could be avoided with an accurate knowledge about each TLR in the pathophysiology of several diseases (12).…”

Section: Discussionmentioning

confidence: 99%

TLR4 and TLR9 Polymorphisms Effect on Inflammatory Response in End-Stage Renal Disease Patients

et al. 2014

View full text Add to dashboard Cite

Toll-like receptors (TLRs) playa key role in the response of innate and adaptive immune system to microbial and endogenous ligands. Inflammation is a common feature in end-stage renal disease (ESRD) patients; however, the mechanisms/factors triggering the inflammatory process are still poorly clarified. Our aim was to analyze the impact of the c.-1486T>C and c.896A>G polymorphisms in TLR9 and TLR4 genes, respectively, on the inflammatory response of ESRD patients. Clinical and laboratory evaluation was carried out on 184 ESRD patients. Polymerase chain reaction followed by restriction fragmens length polymorphisms (PCR-RFLP) was employed for genotyping of TLR-4 c.896A>G and TLR-9 c.-1486T>C polymorphisms. The prevalence of AA and AG of TLR4 c.896A>G polymorphism in ESRD patients was 97.8% and 2.2%, respectively. None of the individuals showed a homozygous TLR4 polymorphism. Concerning the TLR9 c.-1486T>C polymorphism, we found that ESRD patients showed a prevalence of TC and CC genotypes of 57.1% and 20.6%, respectively. We found that the heterozygous patients for the TLR4 c.896A>G polymorphism presented an increased level in lymphocyte count, a decrease in neutrophil/lymphocyte ratio and in serum levels of hepcidin. Regarding the TLR9 c.-1486T>C polymorphism, we found that it is associated with decreased white blood cell and neutrophil counts, ferritin and CRP serum levels, and with an increase in serum levels of creatinine. Our data suggest that the presence of the studied polymorphisms is associated with a decreased inflammatory response in ESRD patients under hemodialysis, and, thus its presence might have beneficial effects in ESRD patients. Moreover, our data provide new insights in the role of TLR polymorphisms in renal disease, which might have impact in the near future for the development of innovative therapies.

show abstract

“…Thus, treatment with the TNFblocking antibody, "infl iximab," indicates good clinical response to anti-TNF-alpha agents. This is accompanied with reduced IDO expression (Wolf et al 2004 ;Frazão et al 2013 ).…”

Section: Chronic Immune Activation In Infl Ammatory and Functional Bomentioning

confidence: 91%

Evaluation of Tryptophan Metabolism in Chronic Immune Activation

Engin

2015

Tryptophan Metabolism: Implications for Biological Processes, Health and Disease

View full text Add to dashboard Cite

Chronic immune activation is encountered in different pathologies including granulomatous and functional bowel diseases, cancer, aging, atherosclerosis, and obesity. Persistence of chronic infl ammatory stimuli over time creates a biologic background for immunosenescence and favors neopterin formation with the enhanced tryptophan (Trp) degradation in diseases concomitant with cellular immune activation. Trp degradation leads to the generation of several neuroactive compounds by three distinct pathways.Indoleamine 2,3-dioxygenase (IDO) induction leads to many complex changes within the affected cells resulting in immunosuppression through breakdown of Trp. Thus, neopterin concentrations as well as IDO expression signifi cantly increase in infl ammatory bowel diseases (IBD) such as ulcerative colitis and Crohn's disease.However, irritable bowel syndrome (IBS) is linked with abnormal serotonin functioning and immune activation. In this case, enteric serotonin (5-HT) signaling may be defective and inactivated by the serotonin-selective reuptake transporter (SERT) in the enterocytes. A positive correlation is evident between IBS severity and kynurenine (Kyn) to Trp ratio which is signifi cantly correlated with the rise of interferon (IFN)-gamma.The dual host-protective and tumor-promoting actions of immunity are referred to as cancer immunoediting. IDO-reactive T cells are able to recognize and kill tumor cells as well as IDO-expressing dendritic cells (DCs). IDO activation leads to immunosuppression through breakdown of Trp in the tumor microenvironment and tumor-draining lymph nodes. C-C chemokine receptor type 4 (CCR4)+ forkhead boxp3(Foxp3)+ regulatory T (Treg) cells create a favorable environment for tumor escape from host immune responses. Thus, Foxp3+/IDO+ tumors are associated with more advanced disease.Age-related changes in the immune system are known as immunosenescence. A causal relationship is evident between the Trp metabolism and immune defi ciency in elderly. Eventually, the reduced serum Trp concentrations and increased Kyn levels indicate increased chronic low-grade infl ammation in elderly. In this case,

show abstract

Toll-Like Receptors’ Pathway Disturbances are Associated with Increased Susceptibility to Infections in Humans

Cited by 72 publications

References 175 publications

Innate immunity in diabetes and diabetic nephropathy

Innate immunity in diabetes and diabetic nephropathy

TLR4 and TLR9 Polymorphisms Effect on Inflammatory Response in End-Stage Renal Disease Patients

Evaluation of Tryptophan Metabolism in Chronic Immune Activation

Contact Info

Product

Resources

About