Toll-like receptors and diabetes: a therapeutic perspective

2011 ◽  
Vol 122 (5) ◽  
pp. 203-214 ◽  
Author(s):  
Mohan R. Dasu ◽  
Sandra Ramirez ◽  
Roslyn R. Isseroff
Keyword(s):  
Immune Responses ◽  
Inflammatory Responses ◽  
Adaptive Immune Response ◽  
Innate Immune ◽  
Undiagnosed Diabetes ◽  
Innate Immune Responses ◽  
Toll Like Receptors ◽  
Adaptive Immune ◽  
Molecular Patterns ◽  
Therapeutic Perspective

Diabetes is a mutifactorial metabolic disorder that leads to a number of complications. Diabetes is estimated to affect 36 million people in the U.S.A., and the prevalence of diagnosed and undiagnosed diabetes is at 9.3% and continues to rise. Evidence from experimental animal models as well as humans has indicated that systemic inflammation plays a role in the pathophysiological processes of diabetes and is facilitated by innate immune responses. TLRs (Toll-like receptors) are key innate immune receptors that recognize conserved PAMPs (pathogen-associated molecular patterns), induce inflammatory responses essential for host defences and initiate an adaptive immune response. Although TLR expression is increased in a plethora of inflammatory disorders, the effects of metabolic aberrations on TLRs and their role in diabetes and its complications is still emerging. In the present paper, we provide a systematic review on how TLRs play a detrimental role in the pathogenic processes [increased blood sugar, NEFAs (non-esterified ‘free’ fatty acids), cytokines and ROS (reactive oxygen species)] that manifest diabetes. Furthermore, we will highlight some of the therapeutic strategies targeted at decreasing TLRs to abrogate inflammation in diabetes that may eventually result in decreased complications.

scholarly journals Functional Roles of Syk in Macrophage-Mediated Inflammatory Responses

2014 ◽  
Vol 2014 ◽  
pp. 1-12 ◽  
Author(s):  
Young-Su Yi ◽  
Young-Jin Son ◽  
Chongsuk Ryou ◽  
Gi-Ho Sung ◽  
Jong-Hoon Kim ◽  
...  
Keyword(s):  
Immune Responses ◽  
Inflammatory Responses ◽  
Inflammatory Diseases ◽  
Innate Immune ◽  
Innate Immune Responses ◽  
Adaptive Immune Responses ◽  
Functional Roles ◽  
Pathogen Invasion ◽  
Adaptive Immune ◽  
Biological Responses

Inflammation is a series of complex biological responses to protect the host from pathogen invasion. Chronic inflammation is considered a major cause of diseases, such as various types of inflammatory/autoimmune diseases and cancers. Spleen tyrosine kinase (Syk) was initially found to be highly expressed in hematopoietic cells and has been known to play crucial roles in adaptive immune responses. However, recent studies have reported that Syk is also involved in other biological functions, especially in innate immune responses. Although Syk has been extensively studied in adaptive immune responses, numerous studies have recently presented evidence that Syk has critical functions in macrophage-mediated inflammatory responses and is closely related to innate immune response. This review describes the characteristics of Syk-mediated signaling pathways, summarizes the recent findings supporting the crucial roles of Syk in macrophage-mediated inflammatory responses and diseases, and discusses Syk-targeted drug development for the therapy of inflammatory diseases.

Toll-like receptors as a therapeutic target in cancer, infections and inflammatory diseases

Immunotherapy ◽  
2020 ◽  
Vol 12 (5) ◽  
pp. 311-322
Author(s):  
Lizdany Flórez-Álvarez ◽  
Lanie Ruiz-Perez ◽  
Natalia Taborda ◽  
Juan C Hernandez
Keyword(s):  
Immune Response ◽  
Immune Responses ◽  
Inflammatory Diseases ◽  
Adaptive Immune Response ◽  
Treatment Strategies ◽  
Toll Like Receptors ◽  
Tumor Treatment ◽  
Special Report ◽  
Adaptive Immune ◽  
Molecular Patterns

Toll-like receptors (TLRs) are widely expressed pattern recognition receptors that bind to conserved molecular patterns expressed by pathogens and damaged cells. After recognition, activated TLRs induce the expression of various proinflammatory and antiviral molecules. Thus, TLRs are potential targets for treatment strategies aimed at boosting the adaptive immune response to vaccines, controlling infections, enhancing immune responses during tumor treatment and attenuating immune responses in inflammatory disorders. This Special Report examines the potential of TLRs as targets for the treatment of cancer, infections and inflammatory diseases. Here, we make a particular emphasis on molecules capable of modulating TLRs and their therapeutic applications.

scholarly journals Effects of elevated CO2 levels on lung immune response to organic dust and lipopolysaccaride

2021 ◽  
Author(s):  
David Schneberger ◽  
Upkardeep Singh Pandher ◽  
Brooke Thompson ◽  
Shelley Kirychuk
Keyword(s):  
Immune Responses ◽  
Inflammatory Responses ◽  
Animal Feed ◽  
Weighted Average ◽  
Innate Immune ◽  
Mrna Levels ◽  
Innate Immune Responses ◽  
Organic Dust ◽  
Complex Environments ◽  
Time Weighted Average

Abstract Workplaces with elevated organic dust levels such as animal feed barns also commonly have elevated levels of gasses, such as CO2. Workers exposed to such complex environments often experience respiratory effects that may be due to a combination of respirable factors. We examined the effects of CO2 at the ASHRAE recommended limit (1000 ppm) as well as the EPA 8hr time weighted average limit (5000 ppm) on lung innate immune responses in mice with exposure to inflammatory lipopolysaccharide and organic dust. Mice were nasally instilled with dust extracts or LPS and immediately put into chambers with a constant flow of room air (approx. 430 ppm CO2), 1000 ppm, or 5000 ppm CO2 enriched air. Organic dust exposures tended to show decreased inflammatory responses with 1000 ppm CO2 and increased responses at 5000 ppm CO2. Conversely, LPS with addition of CO2 as low as 1000 ppm tended to inhibit several inflammatory markers. In most cases saline treated animals showed few changes with CO2 exposure, though some changes in mRNA levels were present. This shows that CO2 as low as 1000 ppm CO2 was capable of altering innate immune responses to both LPS and organic dust extracts, but each response was altered in a different fashion.

scholarly journals The neuropeptide receptor NMUR-1 regulates the specificity of C. elegans innate immunity against pathogen infection

2021 ◽  
Author(s):  
Phillip Wibisono ◽  
Shawndra Wibisono ◽  
Jan Watteyne ◽  
Chia-Hui Chen ◽  
Durai Sellegounder ◽  
...  
Keyword(s):  
Innate Immunity ◽  
Immune System ◽  
Immune Responses ◽  
Adaptive Immune System ◽  
Innate Immune ◽  
Innate Immune Responses ◽  
Immune Genes ◽  
C Elegans ◽  
Adaptive Immune ◽  
Functional Assays

A key question in current immunology is how the innate immune system generates high levels of specificity. Like most invertebrates, Caenorhabditis elegans does not have an adaptive immune system and relies solely on innate immunity to defend itself against pathogen attacks, yet it can still differentiate different pathogens and launch distinct innate immune responses. Here, we have found that functional loss of NMUR-1, a neuronal GPCR homologous to mammalian receptors for the neuropeptide neuromedin U, has diverse effects on C. elegans survival against various bacterial pathogens. Transcriptomic analyses and functional assays revealed that NMUR-1 modulates C. elegans transcription activity by regulating the expression of transcription factors, which, in turn, controls the expression of distinct immune genes in response to different pathogens. Our study has uncovered a molecular basis for the specificity of C. elegans innate immunity that could provide mechanistic insights into understanding the specificity of vertebrate innate immunity.

scholarly journals Inflammation and the Gut-Liver Axis in the Pathophysiology of Cholangiopathies

2018 ◽  
Vol 19 (10) ◽  
pp. 3003 ◽  
Author(s):  
Debora Giordano ◽  
Claudio Pinto ◽  
Luca Maroni ◽  
Antonio Benedetti ◽  
Marco Marzioni
Keyword(s):  
Immune Responses ◽  
Inflammatory Responses ◽  
Enterohepatic Circulation ◽  
Intestinal Barrier ◽  
Cell Types ◽  
Innate Immune ◽  
Primary Biliary Cholangitis ◽  
Innate Immune Responses ◽  
Adaptive Immune Cells ◽  
Bacterial Products

Cholangiocytes, the epithelial cells lining the bile ducts, represent the unique target of a group of progressive diseases known as cholangiopathies whose pathogenesis remain largely unknown. In normal conditions, cholangiocytes are quiescent and participate to the final bile volume and composition. Following exogenous or endogenous stimuli, cholangiocytes undergo extensive modifications of their phenotype. Reactive cholangiocytes actively proliferate and release a set of proinflammatory molecules, which act in autocrine/paracrine manner mediating the cross-talk with other liver cell types and innate and adaptive immune cells. Cholangiocytes themselves activate innate immune responses against gut-derived microorganisms or bacterial products that reach the liver via enterohepatic circulation. Gut microbiota has been implicated in the development and progression of the two most common cholangiopathies, i.e., primary sclerosing cholangitis (PSC) and primary biliary cholangitis (PBC), which have distinctive microbiota composition compared to healthy individuals. The impairment of intestinal barrier functions or gut dysbiosis expose cholangiocytes to an increasing amount of microorganisms and may exacerbate inflammatory responses thus leading to fibrotic remodeling of the organ. The present review focuses on the complex interactions between the activation of innate immune responses in reactive cholangiocytes, dysbiosis, and gut permeability to bacterial products in the pathogenesis of PSC and PBC.

Cellular and molecular insights on the regulation of innate immune responses to experimental aspergillosis in chicken and turkey poults

2020 ◽  
Author(s):  
Tobias Vahsen ◽  
Laura Zapata ◽  
Rodrigo Guabiraba ◽  
Elise Melloul ◽  
Nathalie Cordonnier ◽  
...  
Keyword(s):  
Immune Responses ◽  
Aspergillus Fumigatus ◽  
Inflammatory Responses ◽  
Clinical Signs ◽  
Innate Immune ◽  
Innate Immune Responses ◽  
Lung Lesions ◽  
Turkey Poults ◽  
Cd8 T Lymphocyte ◽  
Fungal Immunity

Abstract Across the world, many commercial poultry flocks and captive birds are threatened by infection with Aspergillus fumigatus. Susceptibility to aspergillosis varies among birds; among galliform birds specifically, morbidity and mortality rates seem to be greater in turkeys than in chickens. Little is known regarding the features of avian immune responses after inhalation of Aspergillus conidia, and to date, scarce information on inflammatory responses during aspergillosis exists. Thus, in the present study, we aimed to improve our understanding of the interactions between A. fumigatus and economically relevant galliform birds in terms of local innate immune responses. Intra-tracheal aerosolization of A. fumigatus conidia in turkey and chicken poults led to more severe clinical signs and lung lesions in turkeys, but leukocyte recovery from lung lavages was higher in chickens at 1dpi only. Interestingly, only chicken CD8+ T lymphocyte proportions increased after infection. Furthermore, the lungs of infected chickens showed an early upregulation of pro-inflammatory cytokines, including IL-1β, IFN-γ and IL-6, whereas in turkeys, most of these cytokines showed a downregulation or a delayed upregulation. These results confirmed the importance of an early pro-inflammatory response to ensure the development of an appropriate anti-fungal immunity to avoid Aspergillus dissemination in the respiratory tract. In conclusion, we show for the first time that differences in local innate immune responses between chickens and turkeys during aspergillosis may determine the outcome of the disease. Lay Summary Aspergillus fumigatus infection may cause mortality in poultry, depending on species sensitivity. This study confirms the earlier activation of chickens’ pro-inflammatory effectors to control Aspergillus dissemination, whereas turkeys’ immune response enables the exacerbation of lung lesions.

scholarly journals Osteoarthritis and Toll-Like Receptors: When Innate Immunity Meets Chondrocyte Apoptosis

Biology ◽  
2020 ◽  
Vol 9 (4) ◽  
pp. 65
Author(s):  
Goncalo Barreto ◽  
Mikko Manninen ◽  
Kari K. Eklund
Keyword(s):  
Inflammatory Responses ◽  
Critical Role ◽  
Innate Immune ◽  
Chondrocyte Apoptosis ◽  
Innate Immune Responses ◽  
Toll Like Receptors ◽  
Chondrocyte Death ◽  
Dominant Feature ◽  
Functional Relevance

Osteoarthritis (OA) has long been viewed as a degenerative disease of cartilage, but accumulating evidence indicates that inflammation has a critical role in its pathogenesis. In particular, chondrocyte-mediated inflammatory responses triggered by the activation of innate immune receptors by alarmins (also known as danger signals) are thought to be involved. Thus, toll-like receptors (TLRs) and their signaling pathways are of particular interest. Recent reports suggest that among the TLR-induced innate immune responses, apoptosis is one of the critical events. Apoptosis is of particular importance, given that chondrocyte death is a dominant feature in OA. This review focuses on the role of TLR signaling in chondrocytes and the role of TLR activation in chondrocyte apoptosis. The functional relevance of TLR and TLR-triggered apoptosis in OA are discussed as well as their relevance as candidates for novel disease-modifying OA drugs (DMOADs).

Changes in immune responses to oxidized LDL epitopes during aging in hypercholesterolemic apoE(−/−) mice

2006 ◽  
Vol 291 (6) ◽  
pp. R1644-R1650 ◽  
Author(s):  
Paul C. Dimayuga ◽  
Xiaoning Zhao ◽  
Juliana Yano ◽  
Kuang-Yuh Chyu
Keyword(s):  
Immune Response ◽  
Immune Responses ◽  
Time Course ◽  
Oxidized Ldl ◽  
Adaptive Immune Response ◽  
Adaptive Immune System ◽  
Innate Immune ◽  
Collagen Content ◽  
Aortic Sinus ◽  
Adaptive Immune

Atherosclerosis is a disease associated with aging and is subject to modulation by both the innate and adaptive immune system. The time course of age-dependent changes in immune regulation in the context of atherosclerosis has not been characterized. This study aims to describe alteration of the immune responses to oxidized LDL (oxLDL) during aging that is associated with changes in plaque size and phenotype in apoE(−/−) mice. Mice fed a Western diet were euthanized at 15–17, 36, or >52 wk of age. The descending aortas were stained for assessment of extent of atherosclerosis. Plaque lipid, macrophage, and collagen content were evaluated in aortic sinus lesions. The adaptive immune response to oxLDL was assessed using anti-malondialdehyde-oxidized LDL (MDA-LDL) and copper-oxidized LDL (Cu-oxLDL) IgG, and the innate immune response was assessed using anti-Cu-oxLDL and phosphorylcholine (PC) IgM. Aging was associated with a significant increase in plaque area and collagen content and a decrease in plaque macrophage and lipid content. MDA-LDL IgG significantly increased at 36 wk but was reduced in mice >52 wk. Cu-oxLDL IgG increased with age and IgG-apoB immune complexes were increased in the >52 wk group. Cu-oxLDL and PC IgM significantly increased with age. The expression of splenic cytokines such as IFN-γ, IL-4, and IL-10 increased with age. Our study shows a generalized increase in innate immune responses associated with progression of atherosclerosis and a less inflammatory and less lipid-containing plaque phenotype during aging. The adaptive immune response appeared to be less generalized, with a specific reduction in MDA-LDL IgG.

Identification of a Novel Toll-Like Receptor-Independent Immunoadjuvant Pathway That Depends upon Programmed Cell Death.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 775-775
Author(s):  
Kasper Hoebe ◽  
Edith Janssen ◽  
Bruce Beutler
Keyword(s):  
Immune Response ◽  
Cell Death ◽  
Immune Responses ◽  
Ultraviolet Light ◽  
Adaptive Immune Response ◽  
Type I ◽  
Toll Like Receptors ◽  
Adjuvant Effect ◽  
Tlr Signaling ◽  
Adaptive Immune

Abstract Molecules of microbial origin, and synthetic derivatives of these molecules, have long been used for their immuno-adjuvant effect, and as the key sensors of microbial infection, Toll-like receptors (TLRs) are thought to be essential for adjuvanticity. To the contrary, we now demonstrate the existence of a robust, TLR-independent pathway for adjuvant effect: one that is actually far stronger than the TLR-dependent pathway. Activation of Toll-like receptors (TLRs) and the subsequent production of cytokines such as type I interferon leads to the maturation of dendritic cells (DCs) with upregulation of MHC molecules and costimulatory molecules such as CD40, CD80 and CD86, allowing for optimal interaction between DCs and T-cells. We have determined that TLR signal transduction is minimally dependent upon two adapter proteins, MyD88 and TRIF. In compound homozygous mutant (DKO) mice that lack functional MyD88 and TRIF, there is complete abrogation of all TLR signaling. Such animals therefore comprise a unique model with which to study TLR-independent immune responses. We have now used DKO mice to determine whether an adaptive immune response can be obtained in the absence of TLR signaling. As expected, adjuvanticity obtained via “classical” microbial adjuvants such as complete Freund’s adjuvant or LPS was completely absent in DKO mice. However, subcutaneous administration of syngeneic murine cells expressing ovalbumin and rendered apoptotic by exposure to ultraviolet light resulted in a strong T-cell response in vivo, with impressive production of interferon-g by CD8+ cells and efficient killing of EL-4 cells that expressed CD8-specific OVA peptides, both in wildtype and DKO mice. Adjuvanticity was observed only in the context of apoptosis, in that living cells, not exposed to ultraviolet light before injection, induced little or no response. Moreover, the mixture of the protein antigen with apoptotic cells was insufficient to induce an adaptive immune response; rather, only cells that expressed the protein prior to induction of apoptosis were stimulatory. These results indicate the existence of a specific, cell death-dependent mechanism for adjuvanticity that is TLR-independent and induced by endogenous molecules. We propose that this new adjuvant pathway is of fundamental importance to immune responses at large. We believe that it is required for initiation of the adaptive immune response witnessed in the context of allograft rejection, graft-versus-host disease, and autoimmune diseases as well.

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