Role Of Toll-like Receptors Research Articles

LRRC62 attenuates Toll-like receptor signaling by deubiquitinating TAK1 via CYLD

TGF-β-activated kinase 1 (TAK1) plays a pivotal role in Toll-like receptor (TLR) signaling pathway. However, the mechanisms controlling its activity remain poorly understood. Here, we show that leucine-rich repeat containing 62 (LRRC62), a previously uncharacterized protein, negatively regulates TLR signaling by targeting TAK1. Expression of LRRC62 inhibits the TLRs-induced production of pro-inflammatory cytokine, whereas deficiency in LRRC62 enhances the activation of NF-κB and MAPK signaling and increases the production of pro-inflammatory cytokines. Mechanically, LRRC62 functions as an adaptor to recruit deubiquitinase CYLD to TAK1, thus inhibits the K63-linked poly-ubiquitination and activation of TAK1. Together, our findings uncover an unrecognized mechanism by which LRRC62 antagonizes the activation of TAK1 in a CYLD-mediated deubiquitination-dependent manner, thereby balancing Toll-like receptor signaling to avert overzealous inflammation.

CD14 dictates differential activation of mesenchymal stromal cells through AKT, NF-κB and P38 signals.

Mesenchymal stromal cells (MSCs) widely exist in many tissues and have multiple differentiation potential and immunomodulatory capacities. Recently, MSCs have become promising tools for the treatment of various degenerative disorders and autoimmune diseases. The properties of MSCs could be modified in different microenvironments. Thus, it is important to explore the factors controlling MSC function. The presence of Toll-like receptors (TLRs) in MSCs was demonstrated according to previous studies. Consistently, we also illustrated the expression of TLRs in both murine and human MSCs, and displayed that the expression patterns of TLRs in MSCs from different sources. Furthermore, we explored the role of TLR and TLR signaling pathway in MSCs. Interestingly, activation of TLR4-induced expression of cytokines and some specific genes in MSCs. However, MSCs retained much lower mRNA level compared with macrophages. We explored the expression of CD14 in MSCs from different sources, which played a vital role in TLR4 signaling pathway, and found that MSCs are almost negative for CD14. Moreover, only partial activation of TLR4 signaling pathway was observed in MSCs, with no activation of AKT, NF-κB and P38. Here, in the study we defined TLR expression, function and activation in MSCs, which is critical for designing MSC-based therapies.

Toll-like receptor signaling in hematopoietic stem and progenitor cells.

The innate immune system is essential in the protection against microbial infection and facilitating tissue repair mechanisms. During these stresses, the maintenance of innate immune cell numbers through stress-induced or emergency hematopoiesis is key for our survival. One major mechanism to recognize danger signals is through the activation of Toll-like receptors (TLRs) on the surface of hematopoietic cells, including hematopoietic stem cell (HSC) and hematopoietic progenitor cell (HPC), and nonhematopoietic cells, which recognize pathogen-derived or damaged-induced compounds and can influence the emergency hematopoietic response. This review explores how direct pathogen-sensing by HSC/HPC regulates hematopoiesis, and the positive and negative consequences of these signals. Recent studies have highlighted new roles for TLRs in regulating HSC and HPC differentiation to innate immune cells of both myeloid and lymphoid origin and augmenting HSC and HPC migration capabilities. Most interestingly, new insights as to how acute versus chronic stimulation of TLR signaling regulates HSC and HPC function has been explored. Recent evidence suggests that TLRs may play an important role in many inflammation-associated diseases. This suggests a possible use for TLR agonists or antagonists as potential therapeutics. Understanding the direct effects of TLR signaling by HSC and HPC may help regulate inflammatory/danger signal-driven emergency hematopoiesis.

Expression of toll-like receptors and their regulatory roles in murine cardiac telocytes.

Telocytes, newly discovered in the last decade, are interstitial cells found in numerous organs, with multiple proposed potential biological functions. Toll‐like receptors (TLRs) play an important role in innate and adaptive immunity by recognizing pathogen‐associated molecular patterns (PAMPs). However, it is still unknown whether telocytes express these innate receptors. We sought to determine the expression and role of TLRs in telocytes. In our study, we primarily detected TLR1‐9 expression in telocytes. The proliferation, apoptosis and immunoregulatory activity of telocytes activated with or without TLR ligands were determined. Our results showed that purified telocytes expressed TLR2, TLR3 and TLR5. In particular, telocytes expressed high levels of TLR2 as observed using flow cytometry. When we stimulated telocytes with TLR2 or TLR3 agonists (Pam3CSK4, PolyI:C), iNOS expression was greatly increased after Pam3CSK4 treatment. Additionally, telocyte proliferation was reduced and cell apoptosis was increased after TLR agonist stimulation. A co‐culture experiment showed that supernatant from telocytes pretreated with Pam3CSK4 inhibited T cell activation much more than that from untreated telocytes and this effect was mediated by iNOS. Overall, our results demonstrated TLR expression on telocytes for the first time and provided evidence of an immunoregulatory role of telocytes, indicating their clinical potential.

Role of TLR4/NF-κB signaling pathway in development of postoperative chronic pain in rats: the relationship with expression of Nav1.7 in dorsal root ganglion

Objective To evaluate the role of Toll-like receptor 4 (TLR4)/nuclear factor kappa B (NF-κB) signaling pathway in the development of postoperative chronic pain and the relationship with expression of voltage-gated sodium channel 1.7(Nav1.7)in the dorsal root ganglion (DRG) of rats. Methods Thirty-six clean-grade healthy male Sprague-Dawley rats, aged 9-11 weeks, weighing 200-250 g, were divided into 3 groups (n=12 each) using a random number table method: control group (group C), normal saline group (group NS) and TLR4 antagonist LPS-RS group (group R). Postoperative chronic pain was produced by skin/muscle incision and retraction (SMIR). From 1 day before SMIR to 10 days after SMIR, NS group received continuous intrathecal injection of normal saline 10μl, while R group received continuous intrathecal injection of LPS-RS 20 μg/10 μl.Six rats were randomly selected in each group, and the mechanical pain threshold was measured at 1 day before SMIR and 1, 5, 10, 15 and 20 days after SMIR.The 6 rats left in each group were sacrificed at day 10 after SMIR, and the DRGs of the lumbar segment (L4, 5) were removed for determination of the expression of phosphorylated NF-κB (p-NF-κB) and Nav1.7. Results Compared with group C, the mechanical pain threshold was significantly decreased at 5-20 days after SMIR, and the expression of p-NF-κB and Nav1.7 was up-regulated at 10 days after SMIR in group NS (P<0.01). Compared with group NA, the mechanical pain threshold was significantly increased at 5-20 days after SMIR, and the expression of p-NF-κB and Nav1.7 was down-regulated at 10 days after SMIR in group R (P<0.01). Conclusion Up-regulated expression of Nav1.7 in DRGs after activating TLR4/NF-κB signaling pathway is involved in the development of postoperative chronic pain in rats. Key words: Toll-like receptor 4; NF-kappa B; Pain, postoperative; Ganglia, spinal; Sodium channels

Targeting IRAK4 disrupts inflammatory pathways and delays tumor development in chronic lymphocytic leukemia

Interleukin-1 receptor-associated kinase 4 (IRAK4) plays a critical role in Toll-like receptor (TLR) signal transduction and innate immune responses. Recruitment and subsequent activation of IRAK4 upon TLR stimulation is mediated by the myeloid differentiation primary response 88 (MYD88) adaptor protein. Around 3% of chronic lymphocytic leukemia (CLL) patients have activating mutations of MYD88, a driver mutation in this disease. Here, we studied the effects of TLR activation and the pharmacological inhibition of IRAK4 with ND2158, an IRAK4 competitive inhibitor, as a therapeutic approach in CLL. Our in vitro studies demonstrated that ND2158 preferentially killed CLL cells in a dose-dependent manner. We further observed a decrease in NF-κB and STAT3 signaling, cytokine secretion, proliferation and migration of primary CLL cells from MYD88-mutated and -unmutated cases. In the Eµ-TCL1 adoptive transfer mouse model of CLL, ND2158 delayed tumor progression and modulated the activity of myeloid and T cells. Our findings show the importance of TLR signaling in CLL development and suggest IRAK4 as a therapeutic target for this disease.

Roles of Toll-Like Receptors in Nitroxidative Stress in Mammals.

Free radicals are important antimicrobial effectors that cause damage to DNA, membrane lipids, and proteins. Professional phagocytes produce reactive oxygen species (ROS) and reactive nitrogen species (RNS) that contribute towards the destruction of pathogens. Toll-like receptors (TLRs) play a fundamental role in the innate immune response and respond to conserved microbial products and endogenous molecules resulting from cellular damage to elicit an effective defense against invading pathogens, tissue injury, or cancer. In recent years, several studies have focused on how the TLR-mediated activation of innate immune cells leads to the production of pro-inflammatory factors upon pathogen invasion. Here, we review recent findings that indicate that TLRs trigger a signaling cascade that induces the production of reactive oxygen and nitrogen species.

Toll-like Receptors as Potential Therapeutic Targets in Kidney Diseases.

Toll-like Receptors (TLRs) are members of pattern recognition receptors and serve a pivotal role in host immunity. TLRs response to pathogen-associated molecular patterns encoded by pathogens or damage-associated molecular patterns released by dying cells, initiating an inflammatory cascade, where both beneficial and detrimental effects can be exerted. Accumulated evidence has revealed that TLRs are closely associated with various kidney diseases but their roles are still not well understood. This review updated evidence on the roles of TLRs in the pathogenesis of kidney diseases including urinary tract infection, glomerulonephritis, acute kidney injury, transplant allograft dysfunction and chronic kidney diseases.

PS1145 TARGETED ACTIVATION OF THE PROTEIN PHOSPHATASES SHP-1 AND PP2A ABROGATES CONSTITUTIVE ACTIVATION OF SURVIVAL PATHWAYS IN LARGE GRANULAR LYMPHOCYTE LEUKEMIA (LGLL)

Background: Interleukin-1 receptor-associated kinase 4 (IRAK4) plays a critical role in Toll-like receptor (TLR) signal transduction and innate immune responses. Recruitment and subsequent activation of IRAK4 upon TLR stimulation is mediated by the myeloid differentiation primary response 88 (MYD88) adaptor protein. Around 3% of chronic lymphocytic leukemia (CLL) patients have activating mutations of MYD88, a driver mutation in this disease. Aims: Here, we studied the effects of TLR activation and the pharmacological inhibition of IRAK4 with ND2158, an IRAK4 competitive inhibitor, as a therapeutic approach in CLL. Methods: TLR stimulation was performed with an agonist mix of Pam3CSK4, HKLM, FSL1 and ODN2006. Cytokine secretion and CLL proliferation were assessed by Luminex system and carboxyfluorescein succinimidyl ester staining, respectively. For in vivo studies, the Eμ-TCL1 adoptive transfer mouse model was used. Results: Our in vitro studies demonstrated that ND2158 preferentially killed CLL cells in a dose-dependent manner. We further observed a decrease in NF-κB and STAT3 signaling, cytokine secretion, proliferation and migration of primary CLL cells from MYD88-mutated and –unmutated cases. In the Eμ-TCL1 adoptive transfer mouse model of CLL, ND2158 delayed tumor progression and modulated the activity of myeloid and T cells. Summary/Conclusion: Our findings show the importance of TLR signaling in CLL development and suggest IRAK4 as a therapeutic target for this disease.

365-OR: The NLRP3 Inflammasome Mediates Early Beta-Cell Dysfunction Triggered by Islet Amyloid

Islet amyloid, formed by islet amyloid polypeptide (IAPP) aggregates, may be a trigger of islet inflammation in T2D. In vitro studies using bone marrow-derived macrophages suggest roles for Toll-like receptor 2 (TLR2), and the NLRP3 inflammasome in mediating IAPP aggregate-induced inflammatory gene expression. To assess the impact of amyloid on islet macrophages in vivo, we performed single cell RNA sequencing on sorted islet immune cells from mice which develop islet amyloid via expression of human IAPP (hIAPP-Tg mice); this uncovered robust changes in islet macrophage populations, including upregulation of TLR2 (∼3.0 fold, p=0.002) and NLRP3 (∼2.8 fold, p=0.006) in proinflammatory macrophages. To test whether these receptors mediate IAPP aggregate-induced inflammation and beta cell dysfunction in vivo, we examined if TLR2 or NLRP3 deletion attenuated islet amyloid-induced beta cell dysfunction by crossing hIAPP-Tg mice to Tlr2-/- or Nlrp3-/- mice. Loss of TLR2 did not impact beta cell dysfunction in hIAPP-Tg Tlr2-/- male or female mice compared to hIAPP-Tg Tlr2+/+ littermates, revealing that TLR2 is not necessary for islet-amyloid driven beta cell pathology. In contrast, NLRP3 knockout improved glucose tolerance in young hIAPP-Tg male mice and delayed diabetes onset on high fat diet (HFD) (10.9 vs. 4.9 weeks; p=0.02) compared to hIAPP-Tg littermates with intact NLRP3. However, hIAPP-Tg Nlrp3-/- males eventually developed diabetes and glucose intolerance on long-term HFD. In female hIAPP-Tg mice, in which islet amyloid forms more slowly, NLRP3 deletion markedly improved glucose tolerance after 18 weeks of HFD relative to hIAPP-Tg Nlrp3+/+ controls (AUC: 886 ± 207 vs. 1854 ± 296, p&amp;lt;0.0001). The glycemic benefit of NLRP3 knockout was not due to altered insulin sensitivity, and was absent in non-hIAPP expressing mice, which do not form amyloid. Thus, NLRP3, but not TLR2, mediates early islet amyloid-induced beta cell dysfunction, and may be a therapeutic target for islet inflammation in T2D. Disclosure H.C. Denroche: Advisory Panel; Self; Integrated Nanotherapeutics. N. Kim: Employee; Self; Integrated Nanotherapeutics. K. Yau: None. D. Nackiewicz: None. P.C. Orban: None. I. Suen: None. C.B. Verchere: Advisory Panel; Self; Sirona Biochem. Board Member; Self; Integrated Nanotherapeutics. Funding JDRF; Canadian Institutes of Health Research

Role of TLR4-p38MAPK-NF-κB signaling pathway in sevoflurane-induced decrease in cognitive function of aged rats

Objective To evaluate the role of Toll-like receptor 4(TLR4)-p38 mitogen-assoliated protein kinase (p38MAPK)-nuclear factor kappa B(NF-κB) signaling pathway in sevoflurane-induced decrease in cognitive function of aged rats. Methods Sixty SPF healthy male Sprague-Dawley rats, aged 20 months, weighing 550-750 g, were divided into 5 groups (n=12 each) using a random number table method: control group(C group), sevoflurane group (S group), TAK242 plus sevoflurane group (TS group), SB202190 plus sevoflurane group (SS group), and PDTC plus sevoflurane group (PS group). All the rats were intubated after anesthesia and connected to an animal ventilator.TAK242, SB202190 and PDTC 10 μl were injected into the lateral cerebral ventricle in TS, SS and PS groups, respectively, and normal saline containing the equal volume of DMSO was given in C and S groups.Starting from 10 min after lateral cerebral ventricle injection, 4% sevoflurane was inhaled for 6 h via the tracheal tube, with the inhaled oxygen concentration 30% and oxygen flow rate 2 L/min.The mixture of air and oxygen was inhaled in C group.The learning and memory ability was assessed by Morris water maze test at 7 days after the end of sevoflurane anesthesia, and the escape latency and swimming distance were recorded.Animals were sacrificed after the end of Morris water maze test, and brains were removed and hippocampi were isolated for determination of neural apoptosis (by TUNEL), contents of tumor necrosis factor-alpha (TNF-α) and interleukin-1beta (IL-1β) in hippocampal tissues (by enzyme-linked immunosorbent assay), and expression of caspase-3, phosphorylated p38MAPK (p-p38MAPK), total p38MAPK (t-p38MAPK) and NF-κB in nucleus (by Western blot). The apoptosis rate and p-p38MAPK/t-p38MAPK ratio were calculated. Results Compared with C group, the escape latency and swimming distance were significantly prolonged at each time point, the apoptosis rate and contents of TNF-α and IL-1β were increased, the expression of caspase-3, p-p38MAPK and NF-κB was up-regulated, and p-p38MAPK/t-p38MAPK ratio was increased in the other four groups (P<0.05). Compared with S group, the escape latency and swimming distance were significantly shortened at each time point, the apoptosis rate and contents of TNF-α and IL-1β were decreased, and the expression of caspase-3 was down-regulated in TS, SS and PS groups, the expression of NF-κB was significantly down-regulated in TS and SS groups, and the expression of p-p38MAPK was significantly down-regulated, and p-p38MAPK/t-p38MAPK ratio was decreased in TS group (P<0.05). Compared with TS group, the escape latency and swimming distance were significantly prolonged at each time point, the apoptosis rate and contents of TNF-α and IL-1β were increased, the expression of caspase-3 and p-p38MAPK was up-regulated, and p-p38MAPK/t-p38MAPK ratio was increased in SS and PS groups, and the expression of NF-κB was significantly up-regulated in PS group (P<0.05). The expression of NF-κB was significantly up-regulated in PS group when compared with SS group (P<0.05). Conclusion TLR4-p38MAPK-NF-κB signaling pathway is involved in sevoflurane-induced decrease in cognitive function of aged rats. Key words: Toll-like receptor 4; p38 Mitogen-activated protein kinases; NF-κB; Anesthetics, inhalation; Aged; Cognition disorders

β-Caryophyllene as a Potential Protective Agent Against Myocardial Injury: The Role of Toll-Like Receptors.

Myocardial infarction (MI) remains one of the major causes of mortality around the world. A possible mechanism involved in myocardial infarction is the engagement of Toll-like receptors (TLRs). This study was intended to discover the prospective cardioprotective actions of β-caryophyllene, a natural sesquiterpene, to ameliorate isoproterenol (ISO)-induced myocardial infarction through HSP-60/TLR/MyD88/NFκB pathway. β-Caryophyllene (100 or 200 mg/kg/day orally) was administered for 21 days then MI was induced via ISO (85 mg/kg, subcutaneous) on 20th and 21st days. The results indicated that ISO induced a significant infarcted area associated with several alterations in the electrocardiogram (ECG) and blood pressure (BP) indices and caused an increase in numerous cardiac indicators such as creatine phosphokinase (CPK), creatine kinase-myocardial bound (CK-MB), lactate dehydrogenase (LDH), and cardiac tropinine T (cTnT). In addition, ISO significantly amplified heat shock protein 60 (HSP-60) and other inflammatory markers, such as TNF-α, IL-Iβ, and NFκB, and affected TLR2 and TLR4 expression and their adaptor proteins; Myeloid differentiation primary response 88 (MYD88), and TIR-domain-containing adapter-inducing interferon-β (TRIF). On the other hand, consumption of β-caryophyllene significantly reversed the infarcted size, ECG and BP alterations, ameliorated the ISO elevation in cardiac indicators; it also notably diminished HSP-60, and subsequently TLR2, TLR4, MYD88, and TRIF expression, with a substantial reduction in inflammatory mediator levels. This study revealed the cardioprotective effect of β-caryophyllene against MI through inhibiting HSP-60/TLR/MyD88/NFκB signaling pathways.

Robust antitumor effects of SNA-based T cell therapy

Abstract The use of toll like receptor (TLR) agonists for immunotherapy remains under intense investigation. Activation of TLRs unleash the power of dendritic cells (DCs) to induce a robust antitumor CD8+ T cell response. However, the role of TLRs in CD8+ T cells has been largely overlooked. T cells do express endosomal TLR9, but it is not readily targetable in these non-phagocytic cells. Using the novel delivery platform of spherical nucleic acids (SNAs), we have devised a way to efficiently activate endosomal TLR9 by CpG, while simultaneously delivering tumor antigens to intracellular compartments in T cells. Activation of TLR9 in CD8+ T cells endows them with special properties. First, T cells themselves express appreciable levels of co-stimulatory molecules after activation of CpG derived from SNAs, thereby functioning as antigen presenting cells to cross-prime antigen-specific CD8+ T cells. Second, SNA activated T cells act as chaperones (T chaperones) of SNA material. Through exosomal transfer, T chaperones shuttle CpG and antigen, mouse or human, to bystander DCs for further cross-presentation of antigen. Third, antigen specific T chaperones are highly cytotoxic and resist tumor induced immune suppression. These combined effects of adoptive therapy using tumor antigen specific T chaperones achieve tumor regression in aggressive melanoma models without irradiation or cytokine supplementation, which complicate T cell-based therapies. T chaperones represent a novel cell-based therapy that co-delivers adjuvant and antigen to efficiently boost antitumor CD8+ T cell activity, eliminating the need for viral manipulation and shortens the long, and costly, production time associated with other T cell therapies.

Roles of Toll-like Receptors in Regulating Fibroblastic Reticular Cells Pathobiology during Sepsis

Abstract Fibroblastic reticular cells (FRCs), a subpopulation of stromal cells in lymphoid organs and fat-associated lymphoid clusters (FALCs) in peritoneal fat, play immune-regulatory roles in the host defense. However, the mechanisms underlying the regulation of FRC pathobiology, especially in response to Toll-like receptor (TLR) signaling is unclear. Therefore, we aimed to understand the roles of TLR signaling in FRC pathobiology during sepsis. FALC cells were isolated from mesenteric adipose tissue in wild-type mice before and after cecal ligation and puncture (CLP). The transcriptomic profile of FALC cells were assessed using single cell RNA sequencing. Notably, FRCs were a major population of FALC cells (50 +/− 10.2 % in control, 30 +/− 8.6% in CLP). One population of FRCs were identified in control mice, and two populations of FRCs were identified in CLP mice. According to gene set enrichment analysis, FRCs after CLP are enriched in gene expression associated with inflammatory response and chemotaxis. Interestingly, activation of TLR4 (LPS) and TLR3 (Poly I:C) signaling in mesenteric adipose tissue derived FRCs significantly increased the expression of chemokines known to attract neutrophils (Cxcl2 and Cxcl5), monocytes (Cxcl3), and lymphocytes (Cxcl13 and Ccl20), while activation of TLR9 (ODN1518) significantly decreased these chemokine gene expressions. Importantly, we found similar regulatory effects of TLR3, 4, and 9 on chemokine production in human adipose tissue-derived FRCs. Together, our results indicate that TLRs plays critical roles in regulating chemokine production by FRCs. These data form a knowledge basis upon which to design new therapeutic strategies of FRC-based treatments for sepsis.

CD28-like role for a Toll.

Computational modelling predicts a co-stimulatory role for Toll-like receptor 5 (TLR5) in naive CD4+ T cell activation.

Prognostic impact of toll-like receptors 2 and 4 expression on monocytes in Egyptian patients with hepatocellular carcinoma.

Toll-like receptors (TLRs) have a role in chronic inflammation. Still, little is known about the expression of TLRs in hepatocellular carcinoma (HCC). Herein, we tried to assess the prognostic value of TLR2 and TLR4 expression on circulating monocytes in HCC patients and correlate their levels with some clinical, laboratory data, and treatment outcomes. Forty patients with hepatic focal lesions diagnosed radiologically as HCC by triphasic multislice CT pelviabdominal and chest, and in some patients MRI diffusion and 38 age and sex matching healthy controls were enrolled in the study. Subjects were evaluated for liver functions, alpha-fetoprotein (AFP), imaging, response to different treatments, and overall survival. TLR2 and TLR4 expression by monocytes was detected by flow cytometry. The expression of both TLR2 and TLR4 on monocytes was significantly increased in HCC patients than the controls, in patients with more progressive HCC than those with lower progression and in patients with poor response to treatment than patients with better treatment response. Moreover, their levels showed positive correlations with ALT, AST, and AFP and inverse correlations with the overall survival of HCC patients. The results of the current study suggest that increased expression ofTLR2 and TLR4 on peripheral monocytes might reflect the development and progression of HCC and can be used to indicate poor prognosis. In addition, high expression of TLR2 correlated significantly with poor response to treatment, while high expression of both TLR2 and TLR4 were associated with poor survival. Our findings will help to design more studies on the role of TLRs in HCC pathogenesis and prognosis which may provide new therapeutic targets for HCC.

Extracellular RNAs-TLR3 signaling contributes to cognitive decline in a mouse model of postoperative cognitive dysfunction

Postoperative cognitive dysfunction (POCD) is considered a severe complication after surgery among elderly patients. Toll-like receptor 3 (TLR3) has recently been reported to play an important role in hippocampus-dependent working memory. However, the role of TLR3 in the development of POCD remains unclear. In the current study, we hypothesized that increased extracellular RNAs (exRNAs) during anesthesia and surgical operation, especially double stranded RNAs (dsRNAs), would activate TLR3 signaling pathways and mediate POCD. Using a mouse model of POCD, 20–22 months wild-type (WT) mice were undergoing unilateral nephrectomy and increased TLR3 expression levels and co-localization with neuronal and microglial cells were found in the surgery group compared with the sham group. Compared with WT mice, TLR3 knockout (KO, −/−) mice had improved hippocampus-dependent memory and attenuated production of inflammatory cytokines and apoptosis. Increased exRNAs and/or co-localization with TLR3 were found in both in vitro and in vivo models. Of note, TLR3/dsRNA complex inhibitor administration reduced hippocampal dsRNA level and TLR3 expression, attenuated hippocampal inflammatory cytokines production and apoptosis, and thus improved hippocampus-dependent memory. Our results indicate that exRNAs, especially dsRNAs, present under stressful conditions may trigger TLR3 activation and initiate the downstream inflammatory and apoptotic signaling, and play a substantial role in the development of POCD.

The significance of Toll-like receptors in selected nephropathies

The diseases associated with kidney damage are an increasingly common problem in modern society and complications of chronic renal failure can result in death. Research conducted by many scientific centers, both Polish and foreign, concern the search for possible factors involved in the pathogenesis of glomerulonephritis. One of the possible causes of nephropathy may include the dysfunction of Toll-like receptors (TLRs), which constitute a “bridge” between innate and acquired response. TLRs are involved in receiving signals related to pathogen associated molecular patterns (PAMPs) as well as receiving information related to the danger associated molecular patterns (DAMP). The stimulation of these receptors activates a cascade of reactions in the course of which various mediators, including pro-inflammatory mediators, are produced. The resulting long-lasting inflammation that develops within the glomerulus may cause kidney damage. In both nephropathies caused by excessive production of antibodies in the IgA class, as well as nephropathy induced by diabetes or lupus, the expression of individual TLRs may indicate an inducer of an inflammatory reaction cascade that leads to kidney damage. This article focuses on literature reports that present current views on the role of TLRs in the pathogenesis of the most common nephropathies.

The role of toll-like receptors in multifactorial mechanisms of early and late renal allotransplant injury, with a focus on the TLR4 receptor and mononuclear cells.

The innate immune system is activated before an adaptive immune response. An expression of a particular toll-like receptor (TLR) in a transplanted kidney depends on the localization of specific cells (e.g., endothelium, elements of the nephron structure), recent pathology and the time passed since transplantation. The TLR4 receptor is expressed on renal tubular epithelial (RTE) and endothelial cells, podocytes, blood and interstitial monocytes/macrophages, and dendritic cells. While circulating in blood, some monocytes are attracted and penetrate the transplanted organ, where they supplement the donor's resident macrophages. The intensity of migration depends on the local activation of inflammation in the graft and on the expression of specific receptors on kidney endothelial cells and monocytes/macrophages. The percentage of cells with shifted TLR4 expression usually increases in circulating monocytes. The TLR4 and the biochemical stimulation cascade derived from it in any type of cell, including monocytes, undergo multi-level regulation with feedback loops with other components of the primary system, and are also dependent on the action of immunosuppression. Toll-like receptor 4 senses stimuli that make monocytes contribute differently both to acute/chronic kidney injuries and to the development of tolerance. After kidney transplantation, TLR4 expression and related cytokine production capacity may vary depending on past diseases and oncoming problems. Since conventional immunosuppression does not prevent chronic allograft injury (CAI), peripheral blood monocytes and TLR4 constitute candidates for diagnostic and therapeutic targets. Considering the mutual communication among various elements of the primary immune system, future therapeutic intervention should be directed toward factors directly or indirectly regulating the expression or post-receptor signaling of the TLR4 receptor.

Role of Toll-Like Receptors in Actuating Stem/Progenitor Cell Repair Mechanisms: Different Functions in Different Cells.

Toll-like receptors (TLRs) represent one of the bridges that regulate the cross-talk between the innate and adaptive immune systems. TLRs interact with molecules shared and preserved by the pathogens of origin but also with endogenous molecules (damage/danger-associated molecular patterns (DAMPs)) that derive from injured tissues. This is probably why TLRs have been found to be expressed on several kinds of stem/progenitor cells (SCs). In these cells, the role of TLRs in the regulation of the basal motility, proliferation, differentiation processes, self-renewal, and immunomodulation has been demonstrated. In this review, we analyze the many different functions that the TLRs assume in SCs, pointing out that they can have different effects, depending on the background and on the kind of ligands that they recognize. Moreover, we discuss the TLR involvement in the response of SC to specific tissue damage and in the reparative processes, as well as how the identification of molecules mediating the differential function of TLR signaling could be decisive for the development of new therapeutic strategies. Considering the available studies on TLRs in SCs, here we address the importance of TLRs in sensing an injury by stem/progenitor cells and in determining their behavior and reparative activity, which is dependent on the conditions. Therefore, it could be conceivable that SCs employed in therapy could be potentially exposed to TLR ligands, which might modulate their therapeutic potential in vivo. In this context, to modulate SC proliferation, survival, migration, and differentiation in the pathological environment, we need to better understand the mechanisms of action of TLRs on SCs and learn how to control these receptors and their downstream pathways in a precise way. In this manner, in the future, cell therapy could be improved and made safer.