Inflammasome activation and IL-1β and IL-18 processing during infection.

Interleukin-1β (IL-1β) and IL-18 contribute to host defense against infection by augmenting antimicrobial properties of phagocytes and initiating Th1 and Th17 adaptive immune responses. Protein complexes called inflammasomes activate intracellular caspase-1 autocatalytically, which cleaves the inactive precursors of IL-1β and IL-18 into bioactive cytokines. In this review, we discuss the controversies regarding inflammasome activation and the role of the inflammasome during infection.

Inhibition of caspase-1 activation in Gram-negative sepsis and experimental endotoxemia.

Introduction: Down-regulation of ex-vivo cytokine production is a specific feature in patients with sepsis. Cytokine downregulation was studied focusing on caspase-1 activation and conversion of pro-interleukin-1β into interleukin-1β (IL-1β).

Methods: Peripheral blood mononuclear cells were isolated from a) 92 patients with sepsis mainly of Gram-negative etiology; b) 34 healthy volunteers; and c) 5 healthy individuals enrolled in an experimental endotoxemia study.

Borrelia species induce inflammasome activation and IL-17 production through a caspase-1-dependent mechanism.

Borrelia burgdorferi spirochetes cause Lyme disease, which can result in severe clinical symptoms such as multiple joint inflammation and neurological disorders. IFN-γ and IL-17 have been suggested to play an important role in the host defense against Borrelia, and in the immunopathology of Lyme disease. The caspase-1-dependent cytokine IL-1β has been linked to the generation of IL-17-producing T cells, whereas caspase-1-mediated IL-18 is crucial for IFN-γ production.

Severe Candida spp. infections: new insights into natural immunity.

Invasive infections caused by Candida spp. are associated with high mortality. Colonisation by Candida spp.

Differential susceptibility to lethal endotoxaemia in mice deficient in IL-1α, IL-1β or IL-1 receptor type I.

The role of intereukin-1 (IL-1) in mortality caused by endotoxaemia remains controversial. While IL-1 receptor antagonist (IL-1Ra) protects mice from lethal endotoxaemia, mice deficient in IL-1β (IL-1β⁻( /)⁻) display normal susceptibility to lipopolysaccharide (LPS). The aim of this study was to identify the source of these discrepancies.

The Candida Th17 response is dependent on mannan- and beta-glucan-induced prostaglandin E2.

The fungus Candida albicans is a potent inducer of the T(h)17 response. Prostaglandin E2 (PGE2) is a strong pro-inflammatory mediator, which has proven to be essential for the T(h)17 response. In this study, we have investigated the role of PGE2 in the T(h)17 response induced by C.

T-cell Subsets and Antifungal Host Defenses.

It has been long appreciated that protective immunity against fungal pathogens is dependent on activation of cellular adaptive immune responses represented by T lymphocytes. The T-helper (Th)1/Th2 paradigm has proven to be essential for the understanding of protective adaptive host responses. Studies that have examined the significance of regulatory T cells in fungal infection, and the recent discovery of a new T-helper subset called Th17 have provided crucial information for understanding the complementary roles played by the various T-helper lymphocytes in systemic versus mucosal antifungal host defense.

Diversity: a hallmark of monocyte society.

Murine "inflammatory" and "patrolling" monocytes have specific functional specializations. In this issue of Immunity, Cros et al. (2010) characterize CD14(+) and CD14(dim)CD16(+) monocyte subpopulations as the human "inflammatory" and "patrolling" monocytes that, similarly to their mouse counterparts, are characterized by distinct functional properties.

Pathogenesis of invasive candidiasis.

Purpose Of Review: Disseminated candidiasis remains a life-threatening disease in the ICU. The development of invasive disease with Candida albicans is dependent on multiple factors, such as colonization and efficient host defense at the mucosa. In the present review, we describe the host defense mechanisms against Candida that are responsible for counteracting mucosal invasion, and eliminating the pathogen once invasion has taken place.

Engagement of fatty acids with Toll-like receptor 2 drives interleukin-1β production via the ASC/caspase 1 pathway in monosodium urate monohydrate crystal-induced gouty arthritis.

Objective: The concept that intraarticular crystals of uric acid by themselves trigger episodes of painful gouty arthritis is inconsistent with the clinical reality. Patients with large deposits of monosodium urate monohydrate (MSU) crystals (tophi) do not necessarily experience gouty attacks. In fact, it is the excessive consumption of food or alcohol that elicits the inflammation of the acute gout attack.

Novel strategies for the prevention and treatment of Candida infections: the potential of immunotherapy.

Infections caused by Candida spp. continue to be a substantial cause of disease burden, especially in immunocompromised patients. New approaches are needed to improve the outcome of patients suffering from Candida infections, because it seems unlikely that the established standard treatment will drastically lower the morbidity of mucocutaneous Candida infections and the high mortality associated with invasive candidiasis.

Mycobacterium tuberculosis induces IL-17A responses through TLR4 and dectin-1 and is critically dependent on endogenous IL-1.

In the present study, we dissected the pathways that trigger the IL-17A responses by MTB. Dectin-1 and TLR4 were shown to be involved in MTB-induced IL-17A production, and blockade of the NOD2, TLR2, or MR had no effect on IL-17A. The MAPK Erk, known to mediate transcription of IL-1beta mRNA, was strongly involved in the IL-17A production induced by MTB.

Inflammasome-independent role of apoptosis-associated speck-like protein containing a CARD (ASC) in T cell priming is critical for collagen-induced arthritis.

Rheumatoid arthritis is an autoimmune disease with 1% prevalence in the industrialized world. The contributions of the inflammasome components Nlrp3, ASC, and caspase-1 in the pathogenesis of collagen-induced arthritis have not been characterized. Here, we show that ASC(-/-) mice were protected from arthritis, whereas Nlrp3(-/-) and caspase-1(-/-) mice were susceptible to collagen-induced arthritis.

Differential effects of IL-17 pathway in disseminated candidiasis and zymosan-induced multiple organ failure.

The role of the IL-17 pathway in antifungal host defense is controversial. Several studies suggested that IL-17 is crucial for the protection against Candida infection, whereas other studies reported that IL-17 may contribute to inflammatory pathology and worsening of fungal disease. To address these discrepancies, we assessed the differential role of IL-17 pathway in two models of fungal sepsis: intravenous infection with live Candida albicans, in which fungal growth is the main cause of mortality, and zymosan-induced multiple organ failure, in which the inflammatory pathology drives the mortality.

Reactive oxygen species-independent activation of the IL-1beta inflammasome in cells from patients with chronic granulomatous disease.

Humans with chronic granulomatous diseases (CGDs) due to mutations in p47-phox have defective NADPH activity and thus cannot generate NADPH-dependent reactive oxygen species (ROS). The role of ROS in inflammation is controversial; some in vitro studies suggest that ROS are crucial for secretion of IL-1beta via inflammasome activation, whereas mice defective for ROS and patients with CGD have a proinflammatory phenotype. In this study, we evaluated activation of the IL-1beta inflammasome in cells from CGD patients.

Th17 responses and host defense against microorganisms: an overview.

T helper (Th) 17 cells have recently been described as a third subset of T helper cells, and have provided new insights into the mechanisms that are important in the development of autoimmune diseases and the immune responses that are essential for effective antimicrobial host defense. Both protective and harmful effects of Th17 responses during infection have been described. In general, Th17 responses are critical for mucosal and epithelial host defense against extracellular bacteria and fungi.

Receptor recognition of and immune intracellular pathways for Veillonella parvula lipopolysaccharide.

Veillonella parvula is an anaerobic gram-negative coccus that is part of the normal flora of the animal and human mouth and gastrointestinal and genitourinary tracts. Oral V. parvula is involved in the development of early periodontal disease as well as different types of serious infections.

Transcriptional and inflammasome-mediated pathways for the induction of IL-1beta production by Mycobacterium tuberculosis.

Proinflammatory cytokines of the IL-1 family play an important role for the anti-mycobacterial host defense mechanisms. In the present study we have deciphered the pathways leading from recognition of Mycobacterium tuberculosis to the production and release of IL-1beta, the most important member of the IL-1 family. By stimulating cells defective in various pattern recognition receptors, we could demonstrate that IL-1beta production is induced by M.

The macrophage mannose receptor induces IL-17 in response to Candida albicans.

The cytokine IL-17 controls neutrophil-mediated inflammatory responses. The pattern recognition receptor(s) that induce Th17 responses during infection, in the absence of artificial mitogenic stimulation with anti-CD3/anti-CD28 antibodies, remain obscure. We investigated the innate immune receptors and pathogen-associated molecular patterns involved in triggering Th17 responses during pathogen-specific host defense.

Bypassing pathogen-induced inflammasome activation for the regulation of interleukin-1beta production by the fungal pathogen Candida albicans.

Background: Interleukin (IL)-1beta has an important role in antifungal defense mechanisms. The inflammasome is thought to be required for caspase-1 activation and processing of the inactive precursor pro-IL-1beta. The aim of the present study was to investigate the pathways of IL-1beta production induced by Candida albicans in human monocytes.

Differential requirement for the activation of the inflammasome for processing and release of IL-1beta in monocytes and macrophages.

The processing of pro-interleukin-1beta depends on activation of caspase-1. Controversy has arisen whether Toll-like receptor (TLR) ligands alone can activate caspase-1 for release of interleukin-1beta (IL-1beta). Here we demonstrate that human blood monocytes release processed IL-1beta after a one-time stimulation with either TLR2 or TLR4 ligands, resulting from constitutively activated caspase-1 and release of endogenous adenosine triphosphate.

The role of NLRs and TLRs in the activation of the inflammasome.

Background: Interleukin-1 beta is one of the most important pro-inflammatory cytokines. In contrast to other cytokines, activation of IL-1 beta requires processing from an inactive precursor by the cysteine protease caspase-1. Caspase-1 forms a protein platform called the inflammasome, together with proteins of the nucleotide-binding oligomerization domain-like receptor (NLR) family.

Redundant role of TLR9 for anti-Candida host defense.

The role of Toll-like receptor-9 (TLR9) in the recognition of Candida albicans and anti-Candida host defense was investigated in a murine model of disseminated candidiasis and in human peripheral blood mononuclear cells (PBMC). Blocking TLR9 by a specific inhibitor of human TLR9 or stimulation of cells isolated from TLR9-deficient (TLR9-/-) mice resulted in a 20-30% reduction in cytokine production induced by C. albicans.

Host-microbe interactions: innate pattern recognition of fungal pathogens.

The recognition of fungi is mediated by germline pattern recognition receptors (PRRs) such as Toll-like receptors and lectin receptors that interact with conserved structures of the microorganisms, the pathogen-associated molecular patterns (PAMPs). Subsequently, PRRs activate intracellular signals that collaborate for the efficient activation of the host defense. The specificity of these responses is achieved through the activation of a particular mosaic of PRRs, that is determined by the available fungal PAMPs and the innate immune cells involved.