Suzanne L. Cassel

The Nalp3 inflammasome is essential for the development of silicosis

Inhalation of crystalline silica and asbestos is known to cause the progressive pulmonary fibrotic disorders silicosis and asbestosis, respectively. Although alveolar macrophages are believed to initiate these inflammatory responses, the mechanism by which this occurs has been unclear. Here we show that the inflammatory response and subsequent development of pulmonary fibrosis after inhalation of silica is dependent on the Nalp3 inflammasome. Stimulation of macrophages with silica results in the activation of caspase-1 in a Nalp3-dependent manner. Macrophages deficient in components of the Nalp3 inflammasome were incapable of secreting the proinflammatory cytokines interleukin (IL)-1β and IL-18 in response to silica. Similarly, asbestos was capable of activating caspase-1 in a Nalp3-dependent manner. Activation of the Nalp3 inflammasome by silica required both an efflux of intracellular potassium and the generation of reactive oxygen species. This study demonstrates a key role for the Nalp3 inflammasome in the pathogenesis of pneumoconiosis.

Cutting Edge: Candida albicans Hyphae Formation Triggers Activation of the Nlrp3 Inflammasome

The proinflammatory cytokine IL-1β plays an important role in antifungal immunity; however, the mechanisms by which fungal pathogens trigger IL-1β secretion are unclear. In this study we show that infection with Candida albicans is sensed by the Nlrp3 inflammasome, resulting in the subsequent release of IL-1β. The ability of C. albicans to switch from a unicellular yeast form into a filamentous form is essential for activation of the Nlrp3 inflammasome, as C. albicans mutants incapable of forming hyphae were defective in their ability to induce macrophage IL- 1β secretion. Nlrp3-deficient mice also demonstrated increased susceptibility to infection with C. albicans, which is consistent with a key role for Nlrp3 in innate immune responses to the pathogen C. albicans.

Mechanism of NLRP3 inflammasome activation.

Inflammasomes continue to generate interest in an increasing number of disciplines owing to their unique ability to integrate a myriad of signals from pathogen‐ and damage‐associated molecular patterns into a proinflammatory response. This potent caspase‐1–dependent process is capable of activating the innate immune system, initiating pyroptosis (an inflammatory form of programmed cell death), and shaping adaptive immunity. The NLRP3 inflammasome is the most thoroughly studied of the inflammasome complexes that have been described thus far, perhaps owing to its disparate assortment of agonists. This review highlights our current understanding of the mechanisms of both priming and activation of the NLRP3 inflammasome.

Sensing Pathogens and Danger Signals by the Inflammasome

The NLR (nucleotide-binding domain leucine-rich repeat containing) family of intracellular sensors is a crucial component of the innate immune system. A number of NLR family members can form multiprotein complexes, called inflammasomes, and are capable of activating the cysteine protease caspase-1 in response to a wide range of stimuli including both microbial and self-molecules. Caspase-1 activation leads to processing and secretion of the proinflammatory cytokines interleukin-1beta (IL-1beta) and IL-18, which play crucial roles in host defense to infectious insults. Dysregulation of the inflammasome has also been linked to a number of autoinflammatory and autoimmune disorders. Recent advances in the inflammasome field will be discussed in this review.

Sensing damage by the NLRP3 inflammasome

Summary:  The NLRP3 inflammasome is activated in response to a variety of signals that are indicative of damage to the host including tissue damage, metabolic stress, and infection. Upon activation, the NLRP3 inflammasome serves as a platform for activation of the cysteine protease caspase‐1, which leads to the processing and secretion of the proinflammatory cytokines interleukin‐1β (IL‐1β) and IL‐18. Dysregulated NLRP3 inflammasome activation is associated with both heritable and acquired inflammatory diseases. Here, we review new insights into the mechanism of NLRP3 inflammasome activation and its role in disease pathogenesis.

The NLRP3 inflammasome: a sensor of immune danger signals.

The innate immune system senses danger signals via evolutionary conserved receptors. The nucleotide-binding domain leucine-rich repeat containing receptor (NLR) family is a group of intracellular receptors that drive a wide variety of inflammatory responses. A number of the NLR family members can form inflammasomes, which are multiprotein complexes that can activate caspase-1 and ultimately lead to the processing and secretion of interleukin (IL)-1beta, IL-18 and IL-33. One of the best-studied members of the NLR family is NLRP3 for which a number of divergent activators have recently been described. These and other studies examining the NLRP3 inflammasome will be discussed in this review.

Sterile inflammatory responses mediated by the NLRP3 inflammasome

Through pattern recognition receptors the innate immune system detects disruption of the normal function of the organism and initiates responses directed at correcting these derangements. Cellular damage from microbial or non‐microbial insults causes the activation of nucleotide‐binding domain leucine‐rich repeat containing receptors in multiprotein complexes called inflammasomes. Here we discuss the role of the NLRP3 inflammasome in the recognition of cellular damage and the initiation of sterile inflammatory responses.

Understanding asthma pathogenesis: linking innate and adaptive immunity.

Purpose of review Treatment and even prevention of allergic asthma will require a detailed understanding of disease pathogenesis and in particular identification of factors that govern T-helper type 2 (Th2) immunity. This review defines the priming and differentiation steps necessary to develop antiallergen Th2 immunity and highlights recently identified stimuli that satisfy these requirements. Recent findings Striking discoveries in innate immunity have advanced our understanding of how adaptive immune responses are initiated, yet only recently have these principles been applied to allergic disease. Signaling through certain innate immune receptors, the toll-like receptors (TLR) have been shown to modulate Th2-mediated disease in animal models. The dendritic cell has emerged as the central player in the intricate interplay between the adaptive and innate systems of immunity. Recent studies have also uncovered alternative pathways of initiating allergen sensitization that depend entirely on adaptive, rather than innate immune, triggers. Summary The adaptive immune system cannot initiate a response without the “permission” of the innate immune system, and this holds true for Th2 responses to aeroallergens, although induction of Th2 immunity in response to TLR signaling varies with the type and dose of TLR ligand. However, under conditions of ongoing Th2 inflammation, the adaptive immune system can act as its own adjuvant and provide the necessary activating signals to initiate an immune response to foreign protein antigens. This may be the mechanism underlying the clinically observed phenomenon of polysensitization in atopic patients and provides another therapeutic target in asthma.

Inflammasome-independent IL-1β mediates autoinflammatory disease in Pstpip2-deficient mice.

Significance Chronic recurrent multifocal osteomyelitis (CRMO) is a human disorder of the innate immune system that causes bone inflammation that mimics infectious osteomyelitis. There is a spontaneous mutant mouse model of the disease that is caused by homozygous mutations in the gene Pstpip2. Our studies show that bone inflammation in this model is mediated by the cytokine IL-1β, but that the disease is independent of the nucleotide-binding domain, leucine-rich repeat-containing family, pyrin domain-containing 3 (NLRP3) inflammasome and caspase-1, which is different from most other IL-1–mediated disorders. Further, we implicate neutrophils and neutrophil serine proteases in disease pathogenesis. These data provide a rationale for directly targeting the IL-1 receptor or IL-1β as a therapeutic strategy in CRMO. Chronic recurrent multifocal osteomyelitis (CRMO) is a human autoinflammatory disorder that primarily affects bone. Missense mutation (L98P) of proline-serine-threonine phosphatase-interacting protein 2 (Pstpip2) in mice leads to a disease that is phenotypically similar to CRMO called chronic multifocal osteomyelitis (cmo). Here we show that deficiency of IL-1RI in cmo mice resulted in a significant reduction in the time to onset of disease as well as the degree of bone pathology. Additionally, the proinflammatory cytokine IL-1β, but not IL-1α, played a critical role in the pathology observed in cmo mice. In contrast, disease in cmo mice was found to be independent of the nucleotide-binding domain, leucine-rich repeat-containing family, pyrin domain-containing 3 (NLRP3) inflammasome as well as caspase-1. Neutrophils, but not bone marrow-derived macrophages, from cmo mice secreted increased IL-1β in response to ATP, silica, and Pseudomonas aeruginosa compared with neutrophils from WT mice. This aberrant neutrophil response was sensitive to inhibition by serine protease inhibitors. These results demonstrate an inflammasome-independent role for IL-1β in disease progression of cmo and implicate neutrophils and neutrophil serine proteases in disease pathogenesis. These data provide a rationale for directly targeting IL-1RI or IL-1β as a therapeutic strategy in CRMO.

NFIL3/E4BP4 controls type 2 T helper cell cytokine expression

Type 2 T helper (TH2) cells are critical for the development of allergic immune responses; however, the molecular mechanism controlling their effector function is still largely unclear. Here, we report that the transcription factor NFIL3/E4BP4 regulates cytokine production and effector function by TH2 cells. NFIL3 is highly expressed in TH2 cells but much less in TH1 cells. Production of interleukin (IL)‐13 and IL‐5 is significantly increased in Nfil3−/− TH2 cells and is decreased by expression of NFIL3 in wild‐type TH2 cells. NFIL3 directly binds to and negatively regulates the Il13 gene. In contrast, IL‐4 production is decreased in Nfil3−/− TH2 cells. Increased IL‐13 and IL‐5 together with decreased IL‐4 production by antigen‐stimulated splenocytes from the immunized Nfil3−/− mice was also observed. The ability of NFIL3 to alter TH2 cytokine production is a T‐cell intrinsic effect. Taken together, these data indicate that NFIL3 is a key regulator of TH2 responses.