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Results for “Immunity, Innate”

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PubMed2000

Cutting edge: heat shock protein (HSP) 60 activates the innate immune response: CD14 is an essential receptor for HSP60 activation of mononuclear cells.

Heat shock proteins (HSP), highly conserved across species, are generally viewed as intracellular proteins thought to serve protective functions against infection and cellular stress. Recently, we have reported the surprising finding that human and chlamydial HSP60, both present in human atheroma, can activate vascular cells and macrophages. However, the transmembrane signaling pathways by which extracellular HSP60 may activate cells remains unclear. CD14, the monocyte receptor for LPS, binds numerous microbial products and can mediate activation of monocytes/macrophages and endothelial cells, thus promoting the innate immune response. We show here that human HSP60 activates human PBMC and monocyte-derived macrophages through CD14 signaling and p38 mitogen-activated protein kinase, sharing this pathway with bacterial LPS. These findings provide further insight into the molecular mechanisms by which extracellular HSP may participate in atherosclerosis and other inflammatory disorders by activating the innate immune system.

Animals↗

PubMed2005

Ipr1 gene mediates innate immunity to tuberculosis.

An estimated eight million people are infected each year with the pathogen Mycobacterium tuberculosis, and more than two million die annually. Yet only about 10% of those infected develop tuberculosis. Genetic variation within host populations is known to be significant in humans and animals, but the nature of genetic control of host resistance to tuberculosis remains poorly understood. Previously we mapped a new genetic locus on mouse chromosome 1, designated sst1 (for supersusceptibility to tuberculosis 1). Here we show that this locus mediates innate immunity in sst1 congenic mouse strains and identify a candidate gene, Intracellular pathogen resistance 1 (Ipr1), within the sst1 locus. The Ipr1 gene is upregulated in the sst1 resistant macrophages after activation and infection, but it is not expressed in the sst1 susceptible macrophages. Expression of the Ipr1 transgene in the sst1 susceptible macrophages limits the multiplication not only of M. tuberculosis but also of Listeria monocytogenes and switches a cell death pathway of the infected macrophages from necrosis to apoptosis. Our data indicate that the Ipr1 gene product might have a previously undocumented function in integrating signals generated by intracellular pathogens with mechanisms controlling innate immunity, cell death and pathogenesis.

Animals↗

PubMed2000

The trophoblast is a component of the innate immune system during pregnancy.

Systemic infection with Listeria monocytogenes, a Gram-positive intracellular bacterium, has been used extensively to analyze the innate immune response. Macrophages are central to this response, acting as both the host for and principal defense against this bacterium. During pregnancy L. monocytogenes has a predilection for replication at the maternal-placental interface and consequently is an important cause of fetal morbidity and mortality. However, macrophages are mostly excluded from the murine placenta with neutrophils acting as the main immune effector cell against this bacterium. Colony stimulating factor (CSF)-1, a macrophage growth factor, is synthesized in high concentrations by the uterine epithelium during pregnancy, where it is targeted to trophoblast bearing CSF-1-receptors. To define the involvement of CSF-1 in placental immunity, we infected pregnant mice either homozygous or heterozygous for an inactivating recessive mutation in the gene for CSF-1 (osteopetrotic; Csfmop) with L. monocytogenes. CSF-1 was required to recruit neutrophils to the site of listerial infection in the decidua basalis, and infection by Listeria remained unrestrained in its absence. CSF-1 acted by inducing the trophoblast to synthesize the neutrophil chemoattractants (KC) and macrophage inflammatory protein (MIP)-2. Thus, during pregnancy, trophoblast responsive to CSF-1 acts to organize the maternal immune response to bacterial infection at the utero-placental interface. This previously unknown function indicates that the trophoblast acts as a pregnancy-specific component of the innate immune system.

Animals↗

PubMed2005

New mechanisms of skin innate immunity: ASK1-mediated keratinocyte differentiation regulates the expression of beta-defensins, LL37, and TLR2.

Epidermal keratinocytes differentiate and form a multilayered epidermis, which is the primary barrier between the body and the outer environment. As the epidermis is constantly exposed to a variety of microbial pathogens, its function of resisting microbial pathogens is vital. This characteristic feature is formed during differentiation. Immunohistochemical analysis revealed that the upper epidermis of normal human skin expresses beta-defensins 1-3 and LL37. We hypothesized that epidermal keratinocytes develop an innate immune barrier based on human beta-defensins (hBD) and LL37 during differentiation. To prove this, we introduced an active form of the apoptosis signal-regulating kinase-1 (ASK1), an intracellular regulator of keratinocyte differentiation, into cultured normal human keratinocytes. Transfection of this active form, ASK1-DeltaN, significantly enhanced the expression of hBD1-3 and LL37. In addition, a p38 inhibitor abolished this induction, indicating that the ASK1-p38 cascade regulates the expression of hBD1-3 and LL37. Furthermore, the ASK1-p38 pathway also regulated the expression of Toll-like receptor (TLR)2 in keratinocytes. Contact between S. aureus and keratinocytes resulted in the phosphorylation of p38 and induced the expression of hBD2 and hBD3. Moreover, the p38 inhibitor reduced this induction. In conclusion, the ASK1-p38 cascade regulates the innate immunity of the skin by forming an immune barrier consisting of hBD, LL37, and TLR2 during epidermal differentiation.

Antimicrobial Cationic Peptides↗

PubMed2001

Innate immunity in plants.

Studies of receptors and signal-transduction components that play a role in plant disease resistance have revealed remarkable similarities with innate immunity pathways in insects and mammals. In plants, specific receptors encoded by disease-resistance genes interact with products of microbial effector genes to activate defence responses. Resistance proteins have been found to have motifs in common with components of immune response pathways in mammals and invertebrates, and to rely on similar downstream signalling components. In the future, the sharing of ideas among plant and animal biologists is likely to broaden our understanding of defence responses in diverse organisms.

Animals↗

PubMed2006

Involvement of innate immunity in the pathogenesis of chronic hepatitis C in children.

The aim of the study was to assess the role of selected elements of innate immunity in the pathogenesis of chronic hepatitis C in children. The study comprised 20 children with chronic hepatitis C (group 1), nine healthy hepatitis C virus (HCV) seropositive children (group 2) and 18 healthy children (control group). We evaluated the expression of Toll-like receptor (TLR)2 and TLR4 on peripheral blood neutrophils, and generation of interleukin (IL)-8, IL-10, IL-12 and reactive oxygen species (ROS) by neutrophils. The performed tests demonstrated higher expression of TLR2 and TLR4 on stimulated neutrophils and of TLR4 on non-stimulated neutrophils in group 1 in comparison to HCV seropositive children and controls. In group 1, the expression of TLR2 after granulocyte colony-stimulating factor (GCSF) stimulation showed positive correlation with alanine aminotransferase and asparate aminotransferase activities, while the expression of TLR2 without stimulation and of TLR4 after GCSF stimulation also correlated with necrosis. IL-12 generation by lipopolysachcharide-stimulated neutrophils was higher in group 1 versus controls. In group 1, maximum chemiluminescence (CL) without pre-activation, both spontaneous and after formyl-methionyl-leucyl-phenylanine and phorbol-myristate-acetate (PMA) stimulation, was significantly lower than in the controls. CL after tumour necrosis factor-alpha pre-activation and PMA stimulation was still lower than in the controls, however, after opsonized zymosane stimulation it was significantly higher than in the controls. Our studies suggest the involvement of neutrophils in the pathogenesis of chronic hepatitis C in children. Neutrophils demonstrate increased expression of TLR2 and TLR4 (correlating with the features of hepatocytic damage and intensification of necrosis), inhibition of oxygen metabolism, and after TNF-alpha pre-activation higher ability to produce ROS.

Adolescent↗

PubMed1998

Interleukin-15 as a potential regulator of the innate immune response.

Interleukin-15 (IL-15) is a newly-discovered cytokine that is produced by activated monocytes early in the course of the innate immune response. IL-15 is able to bind to components of the interleukin-2 receptor (IL-2R) despite the fact that it has no sequence homology with IL-2. IL-15 stimulates human natural killer cell proliferation, cytotoxicity, and cytokine production and can substitute for IL-2 under most conditions. In vitro studies indicate that monocyte-derived IL-15 may be an important determinant of IFN-gamma production by NK cells. In addition, IL-15 is able to promote the survival of natural killer cells under serum-free conditions. The IL-15 receptor is a heterotrimeric complex which is composed of the IL-2R beta and gamma chains in combination with a unique alpha chain (IL-15 alpha). The IL-15R alpha chain has strong sequence homology to the IL-2R alpha chain and confers high affinity binding to the IL-15R. In contrast to IL-2, transcript for IL-15 and IL-15 alpha is expressed in a number of tissues and indicates that IL-15 may be an important ligand for cells that express components of the IL-2R.

B-Lymphocytes↗

PubMed2006

Lipopolysaccharide activates an innate immune system response in human adipose tissue in obesity and type 2 diabetes.

UNLABELLED: Type 2 diabetes (T2DM) is associated with chronic low-grade inflammation. Adipose tissue (AT) may represent an important site of inflammation. 3T3-L1 studies have demonstrated that lipopolysaccharide (LPS) activates toll-like receptors (TLRs) to cause inflammation. For this study, we 1) examined activation of TLRs and adipocytokines by LPS in human abdominal subcutaneous (AbdSc) adipocytes, 2) examined blockade of NF-kappaB in human AbdSc adipocytes, 3) examined the innate immune pathway in AbdSc AT from lean, obese, and T2DM subjects, and 4) examined the association of circulating LPS in T2DM subjects. The findings showed that LPS increased TLR-2 protein expression twofold (P<0.05). Treatment of AbdSc adipocytes with LPS caused a significant increase in TNF-alpha and IL-6 secretion (IL-6, CONTROL: 2.7+/-0.5 vs. LPS: 4.8+/-0.3 ng/ml; P<0.001; TNF-alpha, CONTROL: 1.0+/-0.83 vs. LPS: 32.8+/-6.23 pg/ml; P<0.001). NF-kappaB inhibitor reduced IL-6 in AbdSc adipocytes ( CONTROL: 2.7+/-0.5 vs. NF-kappaB inhibitor: 2.1+/-0.4 ng/ml; P<0.001). AbdSc AT protein expression for TLR-2, MyD88, TRAF6, and NF-kappaB was increased in T2DM patients (P<0.05), and TLR-2, TRAF-6, and NF-kappaB were increased in LPS-treated adipocytes (P<0.05). Circulating LPS was 76% higher in T2DM subjects compared with matched controls. LPS correlated with insulin in controls (r=0.678, P<0.0001). Rosiglitazone (RSG) significantly reduced both fasting serum insulin levels (reduced by 51%, P=0.0395) and serum LPS (reduced by 35%, P=0.0139) in a subgroup of previously untreated T2DM patients. In summary, our results suggest that T2DM is associated with increased endotoxemia, with AT able to initiate an innate immune response. Thus, increased adiposity may increase proinflammatory cytokines and therefore contribute to the pathogenic risk of T2DM.

Adipocytes, White↗

PubMed2005

Sodium methyldithiocarbamate inhibits MAP kinase activation through toll-like receptor 4, alters cytokine production by mouse peritoneal macrophages, and suppresses innate immunity.

Sodium methyldithiocarbamate (SMD; trade name, Metam Sodium) is an abundantly used soil fumigant that can cause adverse health effects in humans, including some immunological manifestations. The mechanisms by which SMD acts, and its targets within the immune system are not fully understood. Initial experiments demonstrated that SMD administered by oral gavage substantially decreased IL-12 production and increased IL-10 production induced by lipopolysaccharide in mice. The present study was conducted to further characterize these effects and to evaluate our working hypothesis that the mechanism for these effects involves alteration in signaling through toll-like receptor 4 and that this would suppress innate immunity to infection. SMD decreased the activation of MAP kinases and AP-1 but not NF-kappaB in peritoneal macrophages. The expression of mRNA for IL-1alpha, IL-1beta, IL-18, IFN-gamma, IL-12 p35, IL-12 p40, and macrophage migration inhibitory factor (MIF) was inhibited by SMD, whereas mRNA for IL-10 was increased. SMD increased the IL-10 concentration in the peritoneal cavity and serum and decreased the concentration of IL-12 p40 in the serum, peritoneal cavity, and intracellularly in peritoneal cells (which are >80% macrophages). Similar effects on LPS-induced cytokine production were observed following dermal administration of SMD. The major breakdown product of SMD, methylisothiocyanate (MITC), caused similar effects on cytokine production at dosages as low as 17 mg/kg, a dosage relevant to human exposure levels associated with agricultural use of SMD. Treatment of mice with SMD decreased survival following challenge with non-pathogenic Escherichia coli within 24-48 h, demonstrating suppression of innate immunity.

Animals↗

PubMed2001

Sepsis and evolution of the innate immune response.

OBJECTIVE: To review the role of the Toll-like receptors (TLR) as the principal sensors used by the innate immune system in the context of the pathologic processes underlying sepsis and septic shock. DATA SOURCES: Literature review. DATA SUMMARY: Through the Toll-like receptors, macrophages and other defensive cells "see" endotoxin (TLR4), peptidoglycan (TLR2), and bacterial DNA (TLR9). Representatives of the family predated the divergence of plants and animals and, at that time, had already acquired a defensive function. The strengths and liabilities of the innate immune system, which defends against infection and which also may cause shock and death, are rooted in its ancient origins. In the current era of shock research, the nature of the signals that Toll-like receptors transduce and the effects of genetic variation on microbial sensing are two major challenges.

Animals↗

PubMedDate not supplied

The pathogenicity of Entamoeba histolytica is related to the capacity of evading innate immunity.

The host and parasite factors that influence susceptibility to Entamoeba histolytica infection and disease are not well understood. Entamoeba histolytica pathogenicity has been considered by focusing principally on parasite rather than host factors. Thus, research has concentrated on explaining the molecular differences between pathogenic E. histolytica and non-pathogenic E. dispar. However, the amoeba molecules considered most important for host tissue destruction (amoebapore, galactose/N-acetyl galactosamine inhibitable lectin, and cysteine proteinases) are present in both pathogenic E. histolytica and non-pathogenic E. dispar. In addition, the genetic differences in pathogenicity among E. histolytica isolates are unlikely to completely explain the different outcomes of infection. Considering that the principal difference between pathogenic and non-pathogenic amoebas lies in their surface coats, we propose that pathogenicity of the amoebas is related to the composition and properties of the surface coat components (or pathogen-associated molecular patterns, PAMPs), and the ability of innate immune response to recognize these components and eliminate the parasite. According to this hypothesis, a key feature that may distinguish pathogenic (E. histolytica) from non-pathogenic (E. dispar) strains is whether or not they can overcome innate immune defences. A corollary of this hypothesis is that in susceptible individuals the PAMPs are either not recognized or they are recognized by a set of Toll-like receptors (TLRs) that leads to an inflammatory response. In both cases, the result is tissue damage. On the contrary, in resistant individuals the innate/inflammatory response, induced through the activation of a different set of TLRs, eliminates the parasite.

Animals↗

PubMed2006

Role of MAP kinase-dependent apoptotic pathway in innate immune responses and viral infection.

Mitogen-activated protein (MAP) kinase cascades are multifunctional signalling networks that influence cell growth, differentiation, apoptosis and cellular responses to stress. Apoptosis signal-regulating kinase 1 (ASK1) is a MAP kinase kinase kinase that triggers apoptogenic kinase cascade leading to the phosphorylation/activation of c-Jun N-terminal kinases (JNK) and p38-MAP kinase, which are responsible to induce apoptotic cell death. This pathway plays a pivotal role in the transduction of signals from different apoptotic stimuli. Recently, it has become evident that ASK1 and its downstream pathway are employed in the transduction of signals from Toll-like receptors (TLR) - multistep processes that interfere with different intracellular signalling pathways. TLR are the key proteins that allow mammals to detect pathogens and mediate innate immune responses. In addition, ASK1 and its downstream pathway play a target role in the regulation of apoptosis in some cases of viral infection - AIDS, influenza, hepatitis C and others. In the present review, we summarize current knowledge about the role of ASK1 and its downstream pathway in innate immune responses and viral infection.

Animals↗

PubMed2006

Staphylococcal colonization and infection: homeostasis versus disbalance of human (innate) immunity and bacterial virulence.

PURPOSE OF REVIEW: This review identifies trends in the study of interactions between Staphylococcus aureus and humans. When nasal colonization is in the neutral state, infection clearly represents a state of host-pathogen disbalance. The features leading from apparent homeostatic colonization to pathogenesis are identified at an increasing rate. RECENT FINDINGS: Persistent carriage of S. aureus predisposes to infection but limits bacteraemia-associated mortality. Intermittent carriage is usually imposed and of lesser clinical relevance. The nature and function of several staphylococcal virulence factors have been elucidated and near complete gene catalogues have been established. There does not seem to be a difference in virulence, however, between methicillin-susceptible and resistant S. aureus. Biological selection takes place in the nose and innate immune features relevant to colonization have been discovered. Acquired immunity remains underexposed, but the host factors involved in the host-pathogen interaction have been identified. SUMMARY: Virulence assessment of S. aureus has been facilitated by novel technology: genome-wide inventories of virulence potential can be made and new pathogenic mechanisms have been presumptively identified. These involve invasion procedures but also (innate) immune evasion strategies. These cross-fertilizing developments shed light on the feasibility of novel prophylactic or therapeutic strategies for combating staphylococcal carriage and disease.

Antibodies, Bacterial↗

PubMed2006

Trivalent recognition unit of innate immunity system: crystal structure of trimeric human M-ficolin fibrinogen-like domain.

Ficolins are a kind of pathogen-recognition molecule in the innate immune systems. To investigate the discrimination mechanism between self and non-self by ficolins, we determined the crystal structure of the human M-ficolin fibrinogen-like domain (FD1), which is the ligand-binding domain, at 1.9A resolution. Although the FD1 monomer shares a common fold with the fibrinogen gamma fragment and tachylectin-5A, the Asp-282-Cys-283 peptide bond, which is the predicted ligand-binding site on the C-terminal P domain, is a normal trans bond, unlike the cases of the other two proteins. The trimeric formation of FD1 results in the separation of the three P domains, and the spatial arrangement of the three predicted ligand-binding sites on the trimer is very similar to that of the trimeric collectin, indicating that such an arrangement is generally required for pathogen-recognition. The ligand binding study of FD1 in solution indicated that the recombinant protein binds to N-acetyl-d-glucosamine and the peptide Gly-Pro-Arg-Pro and suggested that the ligand-binding region exhibits a conformational equilibrium involving cis-trans isomerization of the Asp-282-Cys-283 peptide bond. The crystal structure and the ligand binding study of FD1 provide an insight of the self- and non-self discrimination mechanism by ficolins.

Binding Sites↗

PubMed1998

Regulation of an essential innate immune response by the p50 subunit of NF-kappaB.

Recognition of bacterial endotoxin (LPS) elicits multiple host responses, including activation of cells of the innate immune system. LPS exposure occurs repeatedly during septicemia, making strict regulation of gene expression necessary. Such regulation might prevent, for example, the continuous production of proinflammatory cytokines such as tumor necrosis factor (TNF), which could lead to severe vascular collapse. Tolerance to LPS is characterized by a diminished production of TNF during prolonged exposure to LPS, and is therefore likely to represent an essential control mechanism during sepsis. In the present study, which uses mice with genetic deletions of the proteins of NF-kappaB complex, we provide data demonstrating that increased expression of the p50 subunit of NF-kappaB directly results in the downregulation of LPS-induced TNF production. This contention is supported by the following observations: (1) tolerance to LPS is not induced in macrophages from p50-/- mice; (2) long-term pretreatment with LPS does not block synthesis of TNF mRNA in p50-/- macrophages (in contrast to wild-type macrophages); (3) ectopic overexpression of p50 reduces transcriptional activation of the murine TNF promoter; and (4) analysis of the four kappaB sites from the murine TNF promoter demonstrates that binding of p50 homodimers to the positively acting kappaB3 element is associated with development of the LPS-tolerant phenotype. Thus, p50 expression plays a key role in the development of LPS tolerance.

Animals↗

PubMed2004

Liposome-encapsulated CpG oligodeoxynucleotides as a potent adjuvant for inducing type 1 innate immunity.

Unmethylated cytosine-phosphorothioate-guanine oligodeoxynucleotides (CpG-ODNs) exhibit potent immunostimulating activity by binding with Toll-like receptor 9 (TLR9) expressed on antigen-presenting cells. Here, we show that CpG-ODN encapsulated in cationic liposomes (CpG-liposomes) improves its incorporation into CD11c(+) dendritic cells (DCs) and induces enhanced serum interleukin (IL)-12 levels compared with unmodified CpG-ODN. CpG-liposome potently activated natural killer (NK) cells (84.3%) and NKT cells (48.3%) to produce interferon-gamma (IFN-gamma), whereas the same dose of unmodified CpG-ODN induced only low numbers of IFN-gamma-producing NK cells (12.7%) and NKT cells (1.6%) to produce IFN-gamma. In contrast with the NKT cell agonist alpha-galactosylceramide, which induces both IFN-gamma and IL-4 production by NKT cells, CpG-liposome only induced IFN-gamma production by NKT cells. Such potent adjuvant activities of CpG-liposome were absent in TLR9-deficient mice, indicating that CpG-liposome was as effective as CpG-ODN in stimulating type 1 innate immunity through TLR9. In addition to TLR9, at least two other factors, IL-12 production by DCs and direct contact between DCs and NK or NKT cells, were essential for inducing type 1 innate immunity by CpG-liposome. Furthermore, ligation of TLR9 by CpG-liposome coencapsulated with ovalbumin (OVA) caused the induction of OVA-specific CTLs, which exhibited potent cytotoxicity against OVA-expressing tumor cells. These results indicate that CpG-liposome alone or combined with tumor antigen protein provides a promising approach for the prevention or therapy of tumors.

Adjuvants, Immunologic↗

PubMed2006

Innate immune dysfunction in HIV infection: effect of HIV envelope-NK cell interactions.

We have previously described a number of NK cell dysfunctions in HIV-viremic individuals. In the present study, we performed DNA microarray analysis followed by phenotypic and functional characterization in an effort to investigate which HIV envelope glycoproteins (gp120) affect the physiologic functions of NK cells. Upon treatment of NK cells with HIV gp120, DNA microarray analyses indicated up-regulation of several categories of genes that are associated with apoptosis, suppression of both cellular proliferation and survival, as well as down-regulation of genes that play a vital role in cell proliferation, innate immune defense mechanism, and cell survival. Both subtypes of gp120 suppressed NK cell cytotoxicity, proliferation, and the ability to secrete IFN-gamma. NK cells exposed to X4-subtype HIV gp120 showed a significant decrease in the levels of CC chemokines, while exposure to R5-subtype HIV gp120 had minimal effect. Extended exposure to HIV gp120 resulted in apoptosis of NK cells, further validating the microarray data. Our data demonstrate that exposure of NK cells to HIV envelope proteins results in profound cellular abnormalities at the level of gene expression as well as generic cell functions. These findings are likely to be a consequence of a direct HIV gp120-mediated effect on NK cells. Identification of specific surface receptors on NK cells that interact with HIV envelope proteins might explain how HIV is capable of circumventing innate immune defense mechanisms and establishing infection in susceptible individuals.

Apoptosis↗

PubMed2005

Innate immunity conferred by Toll-like receptors 2 and 4 and myeloid differentiation factor 88 expression is pivotal to monosodium urate monohydrate crystal-induced inflammation.

OBJECTIVE: In gout, incompletely defined molecular factors alter recognition of dormant articular and bursal monosodium urate monohydrate (MSU) crystal deposits, thereby inducing self-limiting bouts of characteristically severe neutrophilic inflammation. To define primary determinants of cellular recognition, uptake, and inflammatory responses to MSU crystals, we conducted a study to test the role of Toll-like receptor 2 (TLR-2), TLR-4, and the cytosolic TLR adapter protein myeloid differentiation factor 88 (MyD88), which are centrally involved in innate immune recognition of microbial pathogens. METHODS: We isolated bone marrow-derived macrophages (BMDMs) in TLR-2-/-, TLR-4-/-, MyD88-/-, and congenic wild-type mice, and assessed phagocytosis and cytokine expression in response to endotoxin-free MSU crystals under serum-free conditions. MSU crystals also were injected into mouse synovium-like subcutaneous air pouches. RESULTS: TLR-2-/-, TLR-4-/-, and MyD88-/- BMDMs demonstrated impaired uptake of MSU crystals in vitro. MSU crystal-induced production of interleukin-1beta (IL-1beta), tumor necrosis factor alpha, keratinocyte-derived cytokine/growth-related oncogene alpha, and transforming growth factor beta1 also were significantly suppressed in TLR-2-/- and TLR-4-/- BMDMs and were blunted in MyD88-/- BMDMs in vitro. Neutrophil influx and local induction of IL-1beta in subcutaneous air pouches were suppressed 6 hours after injection of MSU crystals in TLR-2-/- and TLR-4-/- mice and were attenuated in MyD88-/- mice. CONCLUSION: The murine host requires TLR-2, TLR-4, and MyD88 for macrophage activation and development of full-blown neutrophilic, air pouch inflammation in response to MSU crystals. Our findings implicate innate immune cellular recognition of naked MSU crystals by specific TLRs as a major factor in determining the inflammatory potential of MSU crystal deposits and the course of gouty arthritis.

Adaptor Proteins, Signal Transducing↗