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Results for “Immunity, Innate”

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PubMed2005

Evolution and integration of innate immune systems from fruit flies to man: lessons and questions.

Despite broad differences in morphology, ecology and behavior, the fruit fly Drosophila melanogaster and humans show a remarkably high degree of conservation for many molecular, cellular, and developmental aspects of their biology. During the last decade, similarities have also been discovered in some of the mechanisms regulating their innate immune system. These parallels regard mainly the Toll-like receptor family and the intracellular signaling pathways involved in the control of the immune response. However, if the overall similarities are important, the detailed pathogen recognition mechanisms differ significantly between fly and humans, highlighting a complicated evolutionary history of the metazoan innate defenses. In this review, we will discuss the main similarities and differences between the two types of organisms. We hope that this current knowledge will be used as a starting point for a more comprehensive view of innate immunity within the broad variety of metazoan phyla.

Animals↗

PubMed2006

Exercise, inflammation, and innate immunity.

Regular exercise is protective against several chronic diseases ranging from physiologic diseases such as cardiovascular disease to neurologic diseases such as dementia and depression. Exciting recent research points to chronic inflammation as an underlying contributor to many age-related chronic diseases. Cross-sectional and longitudinal studies in animals and humans have shown both an acute and a chronic anti-inflammatory effect. Because innate immunity is a key regulator of inflammatory processes, and chronic inflammation contributes to many illnesses, the effect of regular exercise on innate immunity, most importantly macrophages, holds much promise in terms of defining these mechanisms. Unfortunately, the mechanisms responsible for the observed anti-inflammatory effect of regular exercise have not been elucidated. This article presents several compelling potential mechanisms for the anti-inflammatory effect of exercise, including loss of body fat, reductions in macrophage accumulation in adipose tissue, altered macrophage phenotype in adipose tissue, exercise-induced muscle production of IL-6, or alterations in the balance between the sympathetic and parasympathetic nervous systems. Further investigation to confirm or reject these testable hypotheses will allow better application of exercise therapy to treat and prevent illnesses associated with chronic inflammation.

Animals↗

PubMed2005

Innate immune responses of human tracheal epithelium to Pseudomonas aeruginosa flagellin, TNF-alpha, and IL-1beta.

We measured innate immune responses by primary human tracheal epithelial (HTE) cells grown as confluent, pseudostratified layers during exposure to inflammatory activators on apical vs. basolateral surfaces. Apical Pseudomonas aeruginosa strain PAK (but not flagellin mutant PAK.fliC), flagellin, and flagellin + PAK.fliC activated NF-kappaB and IL-8 expression and secretion. In contrast, HTE cells were insensitive to LPS compared to flagellin. Flagellin activated NF-kappaB in columnar but not basal cells. IL-1beta + TNF-alpha elicited responses similar to those of flagellin. Basolateral flagellin or IL-1beta + TNF-alpha caused 1.5- to 4-fold larger responses, consistent with the fact that NF-kappaB activation occurred in both columnar and basal cells. MyD88 (toll receptor-associated adapter), IL-1 receptor (IL1R)1, and TNF-alpha receptor (TNFR)1 were expressed in columnar and basal cells. ZO-1 was localized to tight junctions of columnar cells but not to basal cells. We infer the following. 1) Flagellin is necessary and sufficient to trigger inflammatory responses in columnar cells during accumulation of P. aeruginosa in the airway surface liquid (ASL); columnar cells express toll-like receptor 5 and MyD88, often associated with flagellin-activated cell signaling. 2) IL-1beta + TNF-alpha in the ASL also activate columnar cells, and these cells also express IL1R1 and TNFR1. 3) Apical flagellin, IL-1beta, and TNF-alpha do not activate basal cells because tight junctions between columnar cells prevent access from the apical surface to the basal cells. 4) Exposure of basolateral surfaces to inflammatory activators elicits larger responses because both columnar and basal cells are activated, likely because both cell types express receptors for flagellin, IL-1beta, and TNF-alpha.

Cell Polarity↗

PubMed2004

TRAIL-R as a negative regulator of innate immune cell responses.

TRAIL receptor (TRAIL-R) signaling has been implicated in inducing apoptosis in tumor cells, but little is understood about its physiological function. Here, we report the generation and characterization of TRAIL-R(-/-) mice, which develop normal lymphocyte populations but possess enhanced innate immune responses. TRAIL-R(-/-) mice exhibited increased clearance of murine cytomegalovirus that correlated with increased levels of IL-12, IFN-alpha, and IFN-gamma. Stimulation of macrophages with Mycobacterium and Toll-like receptor (TLR)-2, -3, and -4, but not TLR9, ligands resulted in high levels of TRAIL upregulation and enhanced cytokine production in TRAIL-R(-/-) cells. The immediate-early TLR signaling events in TRAIL-R(-/-) macrophages and dendritic cells are normal, but I kappa B-alpha homeostatic regulation and NF-kappa B activity at later time points is perturbed. These data suggest that TRAIL-R negatively regulates innate immune responses.

Amino Acid Sequence↗

PubMed2005

Innate immune recognition of the extracellular mucosal pathogen, Helicobacter pylori.

Toll-like receptor (TLR) molecules play a frontline role in the defence of the host against infection by microbial pathogens. These molecules, together with the recently described Nod family proteins, have been shown to trigger innate immune responses in host cells via the recognition of highly conserved microbial structures. TLR4, which is the best-characterised of these "pathogen-recognition molecules" (PRMs), was the first to be shown to recognise a specific microbial component: the lipopolysaccharide (LPS) from Gram-negative bacteria. The molecular specificities of the remaining PRMs have, in nearly all cases, now also been elucidated. Host cells belonging to the myeloid cell lineage are known to be particularly responsive to these microbial constituents. Conversely, other cell types such as epithelial cells, were generally thought to be hypo-responsive to stimulation by such molecules. New evidence suggests that these cells are in fact likely to play a fundamental role in host defence against pathogenic micro-organisms. Indeed, epithelial cells afford an initial barrier against the host microflora, and appear to be able to differentiate between pathogenic and commensal micro-organisms. This review article will discuss current knowledge regarding innate immune responses in epithelial and myeloid cells to the model non-invasive pathogen, Helicobacter pylori, which is a major cause of upper gastrointestinal tract disease in humans.

Animals↗

PubMed2004

The role of matrix metalloproteinase 7 in innate immunity.

Matrix metalloproteinase 7 (MMP-7), or matrilysin, is a secreted protease expressed by glandular and mucosal epithelial cells, keratinocytes, fibroblasts and macrophages. As with other MMPs it can act on the extracellular matrix and thereby regulate cell migration and tissue repair. In addition, MMP-7 has an important role in the maintenance of innate immunity in organs such as the lungs and intestines where it proteolytically activates anti-bacterial peptides such as pro-defensins. MMP-7 is also important for mediating proteolytic release of TNF from macrophages. Consistent with its role in innate immunity, MMP-7 is induced by microbial products and also, unexpectedly, by hypoxia.

Gene Expression Regulation↗

PubMed2004

Evolution of the innate immune system: the worm perspective.

Simple model organisms that are amenable to comprehensive experimental analysis can be used to elucidate the molecular genetic architecture of complex traits. They can thereby enhance our understanding of these traits in other organisms, including humans. Here, we describe the use of the nematode Caenorhabditis elegans as a tractable model system to study innate immunity. We detail our current understanding of the worm's immune system, which seems to be characterized by four main signaling cascades: a p38 mitogen-activated protein kinase, a transforming growth factor-beta-like, a programed cell death, and an insulin-like receptor pathway. Many details, especially regarding pathogen recognition and immune effectors, are only poorly characterized and clearly warrant further investigation. We additionally speculate on the evolution of the C. elegans immune system, taking into special consideration the relationship between immunity, stress responses and digestion, the diversification of the different parts of the immune system in response to multiple and/or coevolving pathogens, and the trade-off between immunity and host life history traits. Using C. elegans to address these different facets of host-pathogen interactions provides a fresh perspective on our understanding of the structure and complexity of innate immune systems in animals and plants.

Amino Acid Sequence↗

PubMed2003

[Innate immunity participation in the pathogenesis of endometriosis].

UNLABELLED: Endometriosis is a serious clinical problem among the women treated because of gynecological reasons. The frequency of its occurrence is estimated for 10-15% of all women at reproductive age. AIM: This study evaluates the chosen phenomenons participating in innate immunity and their role in the pathogenesis of endometriosis. MATERIALS AND METHODS: 42 patients aged 22 to 39 years old treated in Surgical Gynecology Department of Polish Mother Health Centre Research Institute were the study group. Comparative group consisted of 22 age-matched women with no clinical complains. We evaluated production of reactive oxygen intermediates by peripheral blood neutrophils in both groups of women (both spontaneous and stimulated with fMLP) using the chemiluminescence test. We used neutrophils, both resting and previously preactivated with TNF-alpha. The activity of C3 and C4 complement components and total antioxidant status were also measured. RESULTS: Showed that the chemiluminescence values were higher in patients with endometriosis than in comparative group. Preactivation of neutrophils with the use of TNF-alpha was significantly weakened. Both C3 and C4 complement components revealed higher activity in women with endometriosis as compared to those without this disease. Total antioxidant status values were significantly lower in patients with endometriosis than in women from the comparative group. CONCLUSION: Innate immunity may play a significant role in the pathogenesis of endometriosis due to changes in its components activity that are observed in the course of this disease.

Adult↗

PubMed2006

[Outer membrane remodeling of Salmonella typhimurium and host innate immunity].

Pathogenic gram-negative bacteria, including Salmonella typhimurium, remodel their outer membrane to survive within host tissues and phagosomes. The remodeling includes modifications of lipid A, a membrane anchor portion of lipopolysaccharide. Lipid A modifications, such as palmitoylation, deacylation, addition of aminoarabinose, and addition of phosphoethanolamine, are beneficial for salmonellae to resist host innate immunity. Aminoarabinose attachment, phosphoethanolamine attachment, and palmitoylation of lipid A increase salmonellae resistance to cationic antimicrobial peptides. Lipid A deacylation and palmitoylation reduce its ability to activate the Toll-like receptor 4-MD-2 complex, suggesting that these modifications are beneficial for salmonellae to evade host innate immune recognition. These modifications are regulated transcriptionally by the two-component regulatory system PhoP-PhoQ, which is essential for S. typhimurium virulence. Lipid A modifications are also regulated posttranslationally. Aminoarabinose modification of lipid A represses deacylation of lipid A by PagL. The posttranslational regulation may be involved in S. typhimurium pathogenesis.

Animals↗

PubMed1999

In vivo acquired mechanisms of tumor cells local defense against the host innate immunity effectors: implication in specific antitumor immunity.

As shown earlier, the cells transformed in vitro by several different oncogenes, or spontaneously, during in vivo growth in normal hosts would be gradually replaced by the highly-tumorigenic descendants co-expressing high H2O2-catabolizing and PGE2-releasing activities. Acquisition of (H2O2(CA) + PGE(S)) phenotype provides the cells with local defense mechanisms against the host innate immunity effectors. However, it remained unknown, whether the expression of (H2O2(CA) + PGE(S)) phenotype is implicated in susceptibility of tumor cells expressing tumor-specific transplantation antigens to rejection in immune animals. Here, with the use of SV40 in vitro transformed parental cells, negative in expression (H2O2(CA) + PGE(S)) phenotype, and their in vivo selected descendant tumor cell lines expressing this phenotype, we show that: (1) the rates of in vivo selection of the parental SV40 tumor cells expressing (H2O2(CA) + PGE(S)) phenotype are the same in normal and SV40-immune animals; (2) in vivo selected SV40 tumor cells expressing (H2O2(CA) + PGE(S)) phenotype, although they retain specific immunosensitivity, are 100 times less effectively rejected in SV40-immunized animals, as compared with their in vitro SV40-transformed parental cells. Thus, in vivo acquired immunologically non-specific local mechanisms of tumor cells defense against the host innate immunity effectors, significantly decreases the effectiveness of their specific immunorejection.

Animals↗

PubMed2001

Contrasts in tick innate immune responses to Borrelia burgdorferi challenge: immunotolerance in Ixodes scapularis versus immunocompetence in Dermacentor variabilis (Acari: Ixodidae).

The blacklegged tick, Ixodes scapularis Say, transmits the Lyme disease spirochete Borrelia burgdorferi, whereas the American dog tick, Dermacentor variabilis (Say), is unable to transmit the bacterium. We compared the innate immune response of these ticks against spirochetes directly inoculated into the hemocoel cavity of ticks. In I. scapularis, some Borrelia were found associated with hemocytes, while numerous other spiral-shaped, intact bacteria remained free in the hemolymph. In contrast, in D. variabilis only remnants of the bacteria were evident in the hemolymph, indicating lysis; intact spirochetes were rare. Spirochetes were observed bound to or within the organs of both tick species, although many more spirochetes were found associated with the I. scapularis organs. The few spirochetes observed with the D. variabilis organs appeared to be dead because D. variabilis tissues rarely contained culturable bacteria, unlike I. scapularis tissues. When spirochetes were incubated with I. scapularis hemolymph plasma in vitro, bacterial survival and motility were not reduced. In contrast, incubation of spirochetes with D. variabilis hemolymph plasma resulted in > 50% of the spirochetes becoming nonmotile by 45 min. The differences in the responses of the two different tick species indicate that I. scapularis is immunotolerant when challenged with B. burgdorferi and dependent on a slow phagocytic response to clear Borrelia from the hemolymph. In contrast, D. variabilis is highly immunocompetent (i.e., innate immunity), using plasma borreliacidal factors and a rapid increase in phagocytic cells to clear the infection and limit tissue invasion.

Animals↗

PubMed2026

RADX protects against intestinal inflammation by restraining IFI16-mediated innate immunity.

Genomic instability is increased in patients with inflammatory bowel disease (IBD), yet whether it contributes directly to disease pathogenesis remains unclear. Here, we identify RADX, a structural antagonist to RAD51 and a key regulator of replication fork stability, as a critical suppressor of intestinal inflammation by limiting innate immune sensing of replication-associated DNA damage. RADX deficiency exacerbates experimental colitis, with macrophages serving as the principal mediators of this phenotype. Mechanistically, RADX competes with the DNA sensor IFI16 for binding to single-stranded DNA (ssDNA). Loss of RADX promotes ssDNA accumulation, triggering IFI16-dependent activation of NF-κB signaling and inflammasome assembly, thereby driving intestinal inflammation. Consistent with these findings, two RADX variants identified in patients with IBD associate with reduced RADX protein expression, increased DNA damage signaling, and elevated IL-1β levels. Pharmacological inhibition of RAD51 with RI-1 alleviated colitis in both wild-type and Radx-deficient mice. Together, these findings establish a mechanistic link between genome instability and intestinal inflammation, identify a RADX-IFI16 checkpoint that restrains pathogenic innate immune activation, and nominate modulation of replication stress as a therapeutic strategy for IBD.

Animals↗

PubMed2005

Targeting the innate immune response with improved vaccine adjuvants.

Despite two centuries of vaccine use, only a few adjuvants and delivery systems are licensed for human use. This is partly because traditional vaccines based on attenuated live organisms already have them--their invasiveness provides efficient delivery to antigen-presenting cells and various naturally occurring components of the pathogens stimulate the innate immune system. But consideration of these immune potentiators and delivery systems has become important to the development of new subunit vaccines consisting of isolated antigens. Here we consider rational approaches to the discovery and development of immunostimulatory compounds and vaccine formulations that target innate immune responses.

Adjuvants, Immunologic↗

PubMed2005

Complexity and complementarity of outer membrane protein A recognition by cellular and humoral innate immunity receptors.

Outer membrane protein A (OmpA) is a conserved major component of the outer membrane of Enterobacteriaceae. Here, we report that OmpA from Klebsiella pneumoniae (KpOmpA) activates macrophages and dendritic cells (DCs) in a TLR2-dependent way. However, TLR2 does not account for binding of KpOmpA to innate immune cells. KpOmpA binds the scavenger receptors (SRs) LOX-1 and SREC-I, but not other members of the same family. LOX-1 colocalizes and cooperates with TLR2 in triggering cellular responses. The TLR2-activated functional program includes production of the long pentraxin PTX3, a soluble pattern recognition receptor involved in resistance against diverse pathogens. PTX3, in turn, binds KpOmpA but does not affect recognition of this microbial moiety by cellular receptors. KpOmpA-elicited in vivo inflammation is abrogated in TLR2(-/-) mice and significantly reduced in PTX3(-/-) mice. Thus, SR-mediated KpOmpA recognition and TLR2-dependent cellular activation set in motion a nonredundant PTX3-mediated humoral amplification loop of innate immunity.

Animals↗

PubMed2004

Heterotypic interactions among NACHT domains: implications for regulation of innate immune responses.

Proteins of the NACHT [NAIP (neuronal apoptosis inhibitory protein), CIITA (MHC class II transcription activator), HET-E (incompatibility locus protein from Podospora anserina) and TP1 (telomerase-associated protein)] family may serve as critical pathogen-sensing and signal-transducing molecules within the innate immune system. In the present paper, we show that CLAN [CARD (caspase-recruitment domain), LRR (leucine-rich repeat) and NACHT domain-containing protein], a NACHT-containing protein originally demonstrated to bind and activate pro-caspase 1, is also capable of influencing the functions of other members of the NACHT family. Through heterotypic NACHT-domain interactions, CLAN was found to associate with Nod1, Nod2 and NAC [nucleotide-binding domain and CARD-containing protein; NALP1 (NACHT, LRR and PYRIN protein 1)] when co-expressed in HEK-293T (human embryonic kidney) cells. NF-kappaB (nuclear factor kappaB) reporter assays demonstrated that co-expression of either full-length CLAN or the NACHT domain of CLAN significantly inhibited NF-kappaB activation induced by Nod1 or Nod2 overexpression. In addition, co-expression of CLAN or the NACHT domain of CLAN with Nod1 or Nod2 inhibited the ability of these proteins to generate active IL-1beta (interleukin 1beta) through their association with pro-caspase 1. The NACHT domain of CLAN was demonstrated by co-immunoprecipitation experiments to bind all NACHT domains that were tested, including the NACHT domains from CLAN itself, Nod1, Nod2, cryopyrin, NAC, PAN2 [PAAD [pyrin, AIM (absent-in-melanoma), ASC (apoptosis-associated speck-like protein containing a CARD) and death-domain-like]- and NACHT-containing protein] and NAIP (neuronal apoptosis inhibitory protein). Finally, monocyte-expressed CLAN was found to associate with Nod2 following exposure to bacterial peptidoglycan, implying a regulatory role for interaction of these NACHT proteins in the innate immune response. These studies suggest that by mediating hetero-oligomerization, NACHT domains provide a means by which various NACHT-containing proteins may interact, creating protein-interaction networks that potentially modulate immune responses to invading pathogens.

Adaptor Proteins, Signal Transducing↗

PubMed2005

Parasite cysteine proteinase interactions with alpha 2-macroglobulin or kininogens: differential pathways modulating inflammation and innate immunity in infection by pathogenic trypanosomatids.

Plasma extravasation is a common endothelium response to tissue injury provoked by pathogens. Herein I will review studies showing that host proteinase inhibitors (e.g., alpha2-macroglobulin (alpha2M) or kininogens) interact with protozoan cysteine proteinases (CPs) in extravascular infection sites, linking inflammation to innate immunity by different mechanisms. Using human monocytes as antigen presenting cells, we first demonstrated that alpha2M entrapment of cruzipain, a Trypanosoma cruzi CP, reduced the activation threshold of cruzipain-specific CD4 T cells due to facilitated uptake of alpha2M-cruzipain complexes by the multiscavenger receptor (CD91). More recently, studies of the mechanisms underlying inflammation elicited by T. cruzi revealed that kininogens, once bound to glycosaminoglycans, are not able to efficiently inactivate cruzipain via their inhibitory cystatin-like domains. Instead, we found that cruzipain readily processes surface-bound kininogens, liberating bioactive kinins. Acting as paracrine hormones, kinins vigorously activate host cells through bradykinin (BK) receptors, thus stimulating endocytic uptake of the pathogen. Rather than unilaterally enhancing parasite infectivity, the liberated kinins activate innate immunity by potently stimulating dendritic cell maturation via the BK B2 receptor. The discovery of chagasin, a novel family of endogenous inhibitors expressed by trypanosomatids, is likely another regulatory player involved in the dynamics of the inflammatory response.

Animals↗

PubMed2004

Glucocorticoids suppress inflammation but spare innate immune responses in airway epithelium.

Epithelial cells produce molecules that alter the growth and differentiation of mesenchymal cells, trigger the adhesion to endothelial cells and recruitment of inflammatory leukocytes, and regulate the activation of resident and infiltrating inflammatory cells. Recently, it has become clear that the airway epithelium also participates in innate immune responses. Accumulating evidence suggests that epithelial products such as complement, collectins, lysozyme, lactoferrin, secretory leukocyte protease inhibitor, and defensins can lead to localized destruction of microorganisms. While suppressing systemic adaptive immune responses, glucocorticoids exert little or no inhibitory effect on the ability of the epithelium to express these antimicrobial substances and, in some cases, may even elevate their production. Inhaled glucocorticoids generally profoundly inhibit epithelial cell expression of genes of inflammation, including chemokines, cytokines, and enzymes. Glucocorticoids may enhance the sensitivity of the epithelial surface to Toll-like receptor ligands, and they have been found to induce the expression of surfactant proteins A and D in several in vitro and in vivo model systems. Supporting the concept that glucocorticoids enhance innate immunity while suppressing adaptive immunity, these drugs enhance the survival and/or function of neutrophils and alveolar macrophages but induce the apoptosis of airway dendritic cells.

Administration, Inhalation↗

PubMed2003

STAT3 deletion during hematopoiesis causes Crohn's disease-like pathogenesis and lethality: a critical role of STAT3 in innate immunity.

Signal transducer and activator of transcription 3 (STAT3) is a key transcriptional mediator for many cytokines and is essential for normal embryonic development. We have generated a unique strain of mice with tissue-specific disruption of STAT3 in bone marrow cells during hematopoiesis. This specific STAT3 deletion causes death of these mice within 4-6 weeks after birth with Crohn's disease-like pathogenesis in both the small and large intestine, including segmental inflammatory cell infiltration, ulceration, bowel wall thickening, and granuloma formation. Deletion of STAT3 causes significantly increased cell autonomous proliferation of cells of the myeloid lineage, both in vivo and in vitro. Most importantly, Stat3 deletion during hematopoiesis causes overly pseudoactivated innate immune responses. Although inflammatory cytokines, including tumor necrosis factor alpha and IFN-gamma, are overly produced in these mice, the NAPDH oxidase activity, which is involved in antimicrobial and innate immune responses, is inhibited. The signaling responses to lipopolysaccharide are changed in the absence of STAT3, leading to enhanced NF-kappa B activation. Our results suggest a model in which STAT3 has critical roles in the development and regulation of innate immunity, and deletion of STAT3 during hematopoiesis results in abnormalities in myeloid cells and causes Crohn's disease-like pathogenesis.

Animals↗