• 2′-hydroxy-4′,6′-dimethoxychalcone
• B16F10
• RAW 264.7
• anti-inflammation
• anti-melanogenesis

• 2023RIS-009 Regional Innovation Strategy (RIS)" through the National Research Foundation of Korea funded by the Ministry of Education

• Adaptive immunity
• Endometriosis
• Innate immunity
• LPS/TLR4
• Th17 cells
• Treg cells

• Humans
• Female
• Endometriosis/immunology
• Endometriosis/pathology
• Immunity, Innate
• Adaptive Immunity
• Animals
• T-Lymphocytes, Regulatory/immunology
• Toll-Like Receptors/metabolism
• Toll-Like Receptors/immunology

We recently discovered that (3α,5α)3-hydroxypregnan-20-one (allopregnanolone) inhibits pro-inflammatory toll-like receptor (TLR) activation and cytokine/chemokine production in mouse macrophage RAW264.7 cells. The present studies evaluate neurosteroid actions upon TLR activation in human macrophages from male and female healthy donors. Buffy coat leukocytes were obtained from donors at the New York Blood Center (http://nybloodcenter.org/), and peripheral blood mononuclear cells were isolated and cultured to achieve macrophage differentiation. TLR4 and TLR7 were activated by lipopolysaccharide (LPS) or imiquimod in the presence/absence of allopregnanolone or related neurosteroids and pro-inflammatory markers were detected by ELISA or western blotting. Cultured human monocyte-derived-macrophages exhibited typical morphology, a mixed immune profile of both inflammatory and anti-inflammatory markers, with no sex difference at baseline. Allopregnanolone inhibited TLR4 activation in male and female donors, preventing LPS-induced elevations of TNF-α, MCP-1, pCREB and pSTAT1. In contrast, 3α,5α-THDOC and SGE-516 inhibited the TLR4 pathway activation in female, but not male donors. Allopregnanolone completely inhibited TLR7 activation by imiquimod, blocking IL-1-β, IL-6, pSTAT1 and pIRF7 elevations in females only. 3α,5α-THDOC and SGE-516 partially inhibited TLR7 activation, only in female donors. The results indicate that allopregnanolone inhibits TLR4 and TLR7 activation in cultured human macrophages resulting in diminished cytokine/chemokine production. Allopregnanolone inhibition of TLR4 activation was found in males and females, but inhibition of TLR7 signals exhibited specificity for female donors. 3α,5α-THDOC and SGE-516 inhibited TLR4 and TLR7 pathways only in females. These studies demonstrate anti-inflammatory effects of allopregnanolone in human macrophages for the first time and suggest that inhibition of pro-inflammatory cytokines/chemokines may contribute to its therapeutic actions.

• Animals
• Chemokines/pharmacology
• Cytokines/metabolism
• Female
• Humans
• Imiquimod/pharmacology
• Leukocytes, Mononuclear/metabolism
• Lipopolysaccharides/pharmacology
• Macrophage Activation
• Male
• Mice
• Neurosteroids
• Pregnanolone/pharmacology
• Signal Transduction
• Toll-Like Receptor 4/metabolism
• Toll-Like Receptor 7
• Toll-Like Receptors

• R01 AA024095 NIAAA NIH HHS
• R01 NS108808 NINDS NIH HHS
• National Institute on Alcohol Abuse and Alcoholism
• National Institute of Neurological Disorders and Stroke
• Sage Therapeutics

• TLR
• Th cell
• diabetes
• filariasis
• immunomodulation
• inflammation

Macrophages play a key role in orchestrating the host immune response toward invading organisms or non-self molecules in the oral mucosa. Three-dimensional (3D) oral mucosal equivalents (OME) containing oral fibroblasts and keratinocytes are used extensively to mimic the human oral mucosa where they have been employed to examine innate immune responses to both bacterial and fungal pathogens as well as to biomaterials. Although the presence of immune cells is critical in generating an immune response, very few studies have incorporated leukocytes into OME, and to date, none have contained primary human macrophages. In this study, we report the generation of an immunocompetent OME to investigate immune responses toward bacterial challenge. Primary human monocyte-derived macrophages (MDM) were as responsive to bacterial lipopolysaccharide (LPS) challenge when cultured within a 3D hydrogel in terms of proinflammatory cytokine (IL-6, CXCL8, and TNF-α) gene expression and protein secretion compared with culture as two-dimensional monolayers. MDM were incorporated into a type 1 collagen hydrogel along with oral fibroblasts and the apical surface seeded with oral keratinocytes to generate an MDM-containing OME. Full-thickness MDM-OME displayed a stratified squamous epithelium and a fibroblast-populated connective tissue containing CD68-positive MDM that could be readily isolated to a single-cell population for further analysis by collagenase treatment followed by flow cytometry. When stimulated with LPS, MDM-OME responded with increased proinflammatory cytokine secretion, most notably for TNF-α that increased 12-fold when compared with OME alone. Moreover, this proinflammatory response was inhibited by pretreatment with dexamethasone, showing that MDM-OME are also amenable to drug treatment. Dual-labeled immunofluorescence confocal microscopy revealed that MDM were the sole source of TNF-α production within MDM-OME. These data show functional activity of MDM-OME and illustrate their usefulness for investigations aimed at monitoring the immune response of the oral mucosa to pathogens, biomaterials, and for tissue toxicity and anti-inflammatory drug delivery studies.

• immune response
• infection
• macrophage
• oral mucosa
• tissue engineering

Inflammation is a natural defense process of the innate immune system, associated with the release of proinflammatory cytokines such as interleukin-1β, interleukin-6, interleukin-12 and TNFα; and enzymes including iNOS through the activation and nuclear translocation of NF-κB p65 due to the phosphorylation of IκBα. Regulation of intracellular Ca²⁺ is considered a promising strategy for the prevention of reactive oxygen species (ROS) production and accumulation of DNA double strand breaks (DSBs) that occurs in inflammatory-associated-diseases. Among the metabolites of ellagitannins that are produced in the gut microbiome, urolithin A (UA) has received an increasing attention as a novel candidate with anti-inflammatory and anti-oxidant effects. Here, we investigated the effect of UA on the suppression of pro-inflammatory molecules and NF-κB activation by targeting TLR4 signalling pathway. We also identified the influence of UA on Ca²⁺ entry, ROS production and DSBs availability in murine bone-marrow-derived macrophages challenged with lipopolysaccharides (LPS). We found that UA inhibits IκBα phosphorylation and supresses MAPK and PI3K activation. In addition, UA was able to reduce calcium entry, ROS production and DSBs availability. In conclusion, we suggest that urolithin A is a promising therapeutic agent for treating inflammatory diseases through suppression of NF-κB and preserving DNA through maintaining intracellular calcium and ROS homeostasis.

• Macrophage
• Morphine
• Opioid receptor
• RT-real-time PCR
• TLR4

• cytokine
• liver injury
• macrophage
• toll like receptor
• unfolded protein response

• Animals
• Cell Differentiation/immunology
• Cytokines/biosynthesis
• Macrophages/immunology
• Macrophages/metabolism
• Mice
• Mice, Inbred C57BL
• Stress, Physiological/immunology
• Toll-Like Receptor 4/immunology
• Toll-Like Receptor 4/metabolism
• Unfolded Protein Response/immunology

• R01 CA039621 NCI NIH HHS

C₆₀ fullerene-based nanoformulations are proposed to have a direct toxic effect on tumor cells. Previous investigations demonstrated that C₆₀ fullerene used alone or being conjugated with chemotherapeutic agents possesses a potent anticancer activity. The main aim of this study was to investigate the effect of C₆₀ fullerene and its nanocomplexes with anticancer drugs on human phagocyte metabolic profile in vitro.

Analysis of the metabolic profile of phagocytes exposed to C₆₀ fullerene in vitro revealed augmented phagocytic activity and down-regulated reactive nitrogen species generation in these cells. Additionally, cytofluorimetric analysis showed that C₆₀ fullerene can exert direct cytotoxic effect on normal and transformed phagocytes through the vigorous induction of intracellular reactive oxygen species generation.

Cytotoxic action as well as the pro-oxidant effect of C₆₀ fullerene was more pronounced toward malignant phagocytes. At the same time, C₆₀ fullerenes have the ability to down-regulate the pro-oxidant effect of cisplatin on normal cells. These results indicate that C₆₀ fullerenes may influence phagocyte metabolism and have both pro-oxidant and antioxidant properties.

The antineoplastic effect of C₆₀ fullerene has been observed by direct toxic effect on tumor cells, as well as through the modulation of the functions of effector cells of antitumor immunity.

• Anticancer drugs
• C60 fullerene
• Computer simulation
• Nanocomplexes
• ROS generation
• Transformed monocytes

The onset of hepatic disorders in patients with systemic lupus erythematosus (SLE) is frequent; however, the etiology and liver pathogenesis of SLE remain unknown. In the present study, the role of hepatic deposited immunoglobulin G (IgG) in SLE-derived liver damage was investigated. From a retrospective analysis of the medical records of 404 patients with lupus and from experimental studies on mice models, we found that liver dysfunction is common in SLE and liver damage with IgG deposition spontaneously develops in lupus-prone mice. Liver injury was recreated in mice by injecting IgG from lupus serum intrahepatically. The inflammation intensity in the liver decreased with IgG depletion and the lupus IgG-induced liver inflammation in FcγRIII-deficient mice was comparatively low; while, inflammation was increased in FcγRIIb-deficient mice. Macrophages, Kupffer cells, natural killer cells, and their products, but not lymphocytes, are required for the initiation of SLE-associated liver inflammation. Blocking IgG signaling using a spleen tyrosine kinase (Syk) inhibitor suppressed the liver damage. Our findings provided evidence of spontaneously established liver damage in SLE. They also suggested that hepatic-deposited lupus IgG is an important pathological factor in the development of liver injury and that hepatic inflammation is regulated by the Syk signaling pathway. Thus, Syk inhibition might promote the development of a therapeutic strategy to control liver damage in patients with SLE.

• hepatitis
• immunoglobulin G deposition
• innate immune cells
• spleen tyrosine kinase
• systemic lupus erythematosus

• Toll‐like receptor
• bacterial endotoxin
• endometriosis
• gonadotrophin‐releasing hormone agonist
• menstrual blood

Autocrine or paracrine signaling by beta interferon (IFN-β) is essential for many of the responses of macrophages to pathogen-associated molecular patterns. This feedback loop contributes to pathological responses to infectious agents and is therefore tightly regulated. We demonstrate here that macrophage expression of IFN-β is negatively regulated by mitogen- and stress-activated kinases 1 and 2 (MSK1/2). Lipopolysaccharide (LPS)-induced expression of IFN-β was elevated in both MSK1/2 knockout mice and macrophages. Although MSK1 and -2 promote the expression of the anti-inflammatory cytokine interleukin 10, it did not strongly contribute to the ability of MSKs to regulate IFN-β expression. Instead, MSK1 and -2 inhibit IFN-β expression via the induction of dual-specificity phosphatase 1 (DUSP1), which dephosphorylates and inactivates the mitogen-activated protein kinases p38 and Jun N-terminal protein kinase (JNK). Prolonged LPS-induced activation of p38 and JNK, phosphorylation of downstream transcription factors, and overexpression of IFN-β mRNA and protein were similar in MSK1/2 and DUSP1 knockout macrophages. Two distinct mechanisms were implicated in the overexpression of IFN-β: first, JNK-mediated activation of c-jun, which binds to the IFN-β promoter, and second, p38-mediated inactivation of the mRNA-destabilizing factor tristetraprolin, which we show is able to target the IFN-β mRNA.

• CREB
• DUSP1
• MSK1
• MSK2
• TTP
• beta interferon
• p38 kinases

• Dendritic cells
• Hepatitis C
• Major histocompatibility complex Class-II genes
• Negative regulators
• Non-responders

• Adult
• Antiviral Agents/therapeutic use
• Cells, Cultured
• Dendritic Cells/immunology
• Dendritic Cells/metabolism
• Dendritic Cells/virology
• Down-Regulation
• Female
• Flow Cytometry
• Gene Expression Profiling/methods
• Gene Regulatory Networks
• Genes, MHC Class II
• Genotype
• Hepacivirus/drug effects
• Hepacivirus/genetics
• Hepacivirus/immunology
• Hepatitis C, Chronic/drug therapy
• Hepatitis C, Chronic/genetics
• Hepatitis C, Chronic/immunology
• Hepatitis C, Chronic/metabolism
• Host-Pathogen Interactions
• Humans
• Immunophenotyping/methods
• Male
• Middle Aged
• Phenotype
• Prospective Studies
• Real-Time Polymerase Chain Reaction
• Signal Transduction
• Transcription Factors/genetics
• Transcription Factors/immunology
• Transcription Factors/metabolism

• ERK signaling pathway
• Fomentariol
• Fomes fomentarius
• LPS-induced inflammatory responses
• RAW264.7 cells

• Rural Development Administration, Republic of Korea

• Basophils
• Flagellin
• IL-6
• KU812
• TLR5

• Animals
• Cytokines/biosynthesis
• Gene Expression Regulation/drug effects
• Immunity, Innate/drug effects
• Macrophage Activation/drug effects
• Macrophages/cytology
• Macrophages/drug effects
• Mice
• Morphine/administration & dosage
• RNA, Messenger/biosynthesis
• Toll-Like Receptor 4/biosynthesis
• Toll-Like Receptor 4/isolation & purification

• Caspase-1
• E. coli
• Escherichia coli
• G-CSF
• Inflammation
• Interleukin-18
• JAK2
• LPS
• Leptin
• MAPK
• MDDC
• Monocytes
• NLR-family, pyrin containing 3
• NLRP3
• PAMPs
• PI3K
• PPADS
• STAT
• T helper 1
• T helper 2
• T2DM
• Th1
• Th2
• granulocyte-colony stimulating factor
• janus kinase 2
• lipopolysaccharide
• mitogen-activated protein kinases
• monocyte-derived dendritic cells
• pathogen-activated molecular patterns
• phosphoinositide 3-kinase
• pyrodoxal phosphor-6azo (benzene-2, 4-disulfonic acid) tetrasodium salt hydrate
• signal transducer and activator of transcription
• type-2 diabetes mellitus

• Adenosine Triphosphate/pharmacology
• Caspase 1/metabolism
• Enzyme Activation/drug effects
• Gene Expression Regulation/drug effects
• Humans
• Interleukin-18/genetics
• Interleukin-18/metabolism
• Interleukin-1beta/metabolism
• Leptin/pharmacology
• Lipopolysaccharides/pharmacology
• Monocytes/drug effects
• Monocytes/enzymology
• Monocytes/metabolism
• RNA, Messenger/genetics
• RNA, Messenger/metabolism
• Transcription, Genetic/drug effects

• arthroplasty
• immune response
• murine calvarium
• osteolysis
• polyethylene
• toll-like receptor
• ultra high molecular weight polyethylene
• wear debris

• Toll-like receptors
• bacterial endotoxin
• endometriosis
• endometrium
• infertility
• innate immunity

Atopic dermatitis (AD) is one of the most common and most intensively studied chronic inflammatory skin diseases. Several cofactors, such as an impaired skin barrier function, modifications of the immune system, and a complex genetic background, direct the course of AD. Within this complex network, macrophages play a pivotal role in enhanced susceptibility to cutaneous infections and act as central connecting components in the pathogenesis of AD on the cellular level. In AD, macrophages are known to accumulate in acutely and chronically inflamed skin. During the early and short inflammatory phase, macrophages exert proinflammatory functions like antigen-presenting phagocytosis and the production of inflammatory cytokines and growth factors that facilitate the resolution of inflammation. However, persistence of pro-inflammatory activity and altered function of macrophages result in the development of chronic inflammatory diseases such as AD. The exact mechanism of macrophages activation in these processes is not yet completely understood. Further studies should be performed to clarify the dysregulated mechanism of macrophages activation in AD, and this would allow us to target these cells with versatile functions for therapeutic purpose and improve and control the disease. In this paper, we highlight the new findings on dysregulated function of macrophages and the importance of these cells in the pathogenesis of AD in general and the contribution of these cells in enhanced susceptibility against microbial infections in particular.

• amyloid
• apoptosis
• debris
• inflammation
• microglia
• myelin
• phagocytosis
• synapses

Microglia are the resident brain macrophages and they have been traditionally studied as orchestrators of the brain inflammatory response during infections and disease. In addition, microglia has a more benign, less explored role as the brain professional phagocytes. Phagocytosis is a term coined from the Greek to describe the receptor-mediated engulfment and degradation of dead cells and microbes. In addition, microglia phagocytoses brain-specific cargo, such as axonal and myelin debris in spinal cord injury or multiple sclerosis, amyloid-β deposits in Alzheimer's disease, and supernumerary synapses in postnatal development. Common mechanisms of recognition, engulfment, and degradation of the different types of cargo are assumed, but very little is known about the shared and specific molecules involved in the phagocytosis of each target by microglia. More importantly, the functional consequences of microglial phagocytosis remain largely unexplored. Overall, phagocytosis is considered a beneficial phenomenon, since it eliminates dead cells and induces an anti-inflammatory response. However, phagocytosis can also activate the respiratory burst, which produces toxic reactive oxygen species (ROS). Phagocytosis has been traditionally studied in pathological conditions, leading to the assumption that microglia have to be activated in order to become efficient phagocytes. Recent data, however, has shown that unchallenged microglia phagocytose apoptotic cells during development and in adult neurogenic niches, suggesting an overlooked role in brain remodeling throughout the normal lifespan. The present review will summarize the current state of the literature regarding the role of microglial phagocytosis in maintaining tissue homeostasis in health as in disease.

• amyloid
• apoptosis
• debris
• inflammation
• microglia
• myelin
• phagocytosis
• synapses

Conventionally, signaling through BCR initiates sequence of events necessary for activation and differentiation of B cells. We report an alternative approach, independent of BCR, for stimulating resting B (RB) cells, by involving TLR-2 and CD40 - molecules crucial for innate and adaptive immunity. CD40 triggering of TLR-2 stimulated RB cells significantly augments their activation, proliferation and differentiation. It also substantially ameliorates the calcium flux, antigen uptake capacity and ability of B cells to activate T cells. The survival of RB cells was improved and it increases the number of cells expressing activation induced deaminase (AID), signifying class switch recombination (CSR). Further, we also observed increased activation rate and decreased threshold period required for optimum stimulation of RB cells. These results corroborate well with microarray gene expression data. This study provides novel insights into coordination between the molecules of innate and adaptive immunity in activating B cells, in a BCR independent manner. This strategy can be exploited to design vaccines to bolster B cell activation and antigen presenting efficiency, leading to faster and better immune response.

• Animals
• B-Lymphocytes/cytology
• B-Lymphocytes/immunology
• B-Lymphocytes/metabolism
• B7-1 Antigen/metabolism
• B7-2 Antigen/metabolism
• Biological Transport/immunology
• CD40 Antigens/metabolism
• Calcium/metabolism
• Cell Differentiation/immunology
• Cell Proliferation
• Cytidine Deaminase/metabolism
• Extracellular Signal-Regulated MAP Kinases/metabolism
• Female
• Gene Expression Regulation, Enzymologic/immunology
• Male
• Mice
• Phenotype
• Proto-Oncogene Proteins c-akt/metabolism
• Receptors, Antigen, B-Cell/metabolism
• Signal Transduction/immunology
• T-Lymphocytes, Helper-Inducer/cytology
• T-Lymphocytes, Helper-Inducer/immunology
• T-Lymphocytes, Helper-Inducer/metabolism
• Toll-Like Receptor 1/metabolism
• Toll-Like Receptor 2/metabolism
• Toll-Like Receptor 4/metabolism

• Animals
• Antigens, Surface/biosynthesis
• Cells, Cultured
• Clostridioides difficile/immunology
• Dendritic Cells/cytology
• Dendritic Cells/immunology
• Dendritic Cells/metabolism
• Enterocolitis, Pseudomembranous/immunology
• Enterocolitis, Pseudomembranous/metabolism
• Enterocolitis, Pseudomembranous/microbiology
• Histocompatibility Antigens Class II/biosynthesis
• Interleukins/biosynthesis
• Membrane Glycoproteins/immunology
• Mice
• Mice, Knockout
• Signal Transduction/immunology
• T-Lymphocytes, Helper-Inducer/immunology
• Toll-Like Receptor 4/genetics
• Toll-Like Receptor 4/immunology
• Toll-Like Receptor 4/metabolism

Ineffectiveness of antibiotics in treating neonatal Escherichia coli K1 meningitis and the emergence of antibiotic-resistant strains evidently warrants new prevention strategies. We observed that administration of interleukin (IL)-10 during high-grade bacteremia clears antibiotic-sensitive and -resistant E. coli from blood of infected mice. Micro-CT studies of brains from infected animals displayed gross morphological changes similar to those observed in infected human neonates. In mice, IL-10, but not antibiotic or anti-TNF antibody treatment prevented brain damage caused by E. coli. IL-10 administration elevated CR3 expression in neutrophils and macrophages of infected mice, whereas infected and untreated mice displayed increased expression of FcγRI and TLR2. Neutrophils or macrophages pretreated with IL-10 ex vivo exhibited a significantly greater microbicidal activity against E. coli compared with cells isolated from wild-type or IL-10^−/− mice. The protective effect of IL-10 was abrogated when CR3 was knocked-down in vivo by siRNA. The increased expression of CR3 in phagocytes was caused by inhibition of prostaglandin E-2 (PGE-2) levels, which were significantly increased in neutrophils and macrophages upon E. coli infection. These findings describe a novel modality of IL-10–mediated E. coli clearance by diverting the entry of bacteria via CR3 and preventing PGE-2 formation in neonatal meningitis.

Tyrosine kinase 2 (Tyk2), a central component of Janus kinase/signal transducer and activator of transcription (JAK/STAT) signaling, has major effects on innate immunity and inflammation. Mice lacking Tyk2 are resistant to endotoxin shock induced by lipopolysaccharide (LPS), and Tyk2 deficient macrophages fail to efficiently induce interferon α/β after LPS treatment. However, how Tyk2 globally regulates transcription of downstream target genes remains unknown. Here we examine the regulatory role of Tyk2 in basal and inflammatory transcription by comparing gene expression profiles of peritoneal macrophages from Tyk2 mutant and wildtype control mice that were either kept untreated or exposed to LPS for six hours.

Untreated Tyk2-deficient macrophages exhibited reduced expression of immune response genes relative to wildtype, in particular those that contain interferon response elements (IRF/ISRE), whereas metabolic genes showed higher expression. Upon LPS challenge, IFN-inducible genes (including those with an IRF/ISRE transcription factor binding-site) were strongly upregulated in both Tyk2 mutant and wildtype cells and reached similar expression levels. In contrast, metabolic gene expression was strongly decreased in wildtype cells upon LPS treatment, while in Tyk2 mutant cells the expression of these genes remained relatively unchanged, which exaggerated differences already present at the basal level. We also identified several 5'UR transcription factor binding-sites and 3'UTR regulatory elements that were differentially induced between Tyk2 deficient and wildtype macrophages and that have not previously been implicated in immunity.

Although Tyk2 is essential for the full LPS response, its function is mainly required for baseline expression but not LPS-induced upregulation of IFN-inducible genes. Moreover, Tyk2 function is critical for the downregulation of metabolic genes upon immune challenge, in particular genes involved in lipid metabolism. Together, our findings suggest an important regulatory role for Tyk2 in modulating the relationship between immunity and metabolism.

• activation-induced cytidine deaminase (aid)
• adaptive immunity
• adjuvant
• antibody
• autophagy
• b cell receptor (bcr)
• class-switch dna recombination (csr)
• cd40
• cpg
• cytokine
• innate immunity
• lps
• nf-κb
• somatic hypermutation (shm)
• toll-like receptor (tlr)
• vaccine

• Animals
• Antibodies, Bacterial/immunology
• B-Lymphocytes/immunology
• Humans
• Immunoglobulin Class Switching/genetics
• Immunoglobulin Class Switching/immunology
• Receptors, Antigen, B-Cell/immunology
• Recombination, Genetic/genetics
• Recombination, Genetic/immunology
• T-Lymphocytes/immunology
• Toll-Like Receptors/immunology

• R56 AI079705 NIAID NIH HHS
• R01 AI079705-03 NIAID NIH HHS
• AI 060573 NIAID NIH HHS
• R01 AI045011-09 NIAID NIH HHS
• R01 AI045011 NIAID NIH HHS
• AI 045011 NIAID NIH HHS
• AI 0790705 NIAID NIH HHS
• T32 AI060573 NIAID NIH HHS
• R01 AI079705 NIAID NIH HHS
• R56 AI045011 NIAID NIH HHS
• T32 AI060573-07 NIAID NIH HHS

Tissue fibrosis and chronic inflammation are common causes of progressive organ damage, including progressive renal disease, leading to loss of physiological functions. Recently, it was shown that Toll-like receptor 2 (TLR2) is expressed in the kidney and activated by endogenous danger signals. The expression and function of TLR2 during renal fibrosis and chronic inflammation has however not yet been elucidated. Therefore, we studied TLR2 expression in human and murine progressive renal diseases and explored its role by inducing obstructive nephropathy in TLR2^−/− or TLR2^+/+ mice. We found that TLR2 is markedly upregulated on tubular and tubulointerstitial cells in patients with chronic renal injury. In mice with obstructive nephropathy, renal injury was associated with a marked upregulation and change in distribution of TLR2 and upregulation of murine TLR2 danger ligands Gp96, biglycan, and HMGB1. Notably, TLR2 enhanced inflammation as reflected by a significantly reduced influx of neutrophils and production of chemokines and TGF-β in kidneys of TLR2^−/− mice compared with TLR2^+/+ animals. Although, the obstructed kidneys of TLR2^−/− mice had less interstitial myofibroblasts in the later phase of obstructive nephropathy, tubular injury and renal matrix accumulation was similar in both mouse strains. Together, these data demonstrate that TLR2 can initiate renal inflammation during progressive renal injury and that the absence of TLR2 does not affect the development of chronic renal injury and fibrosis.