Immunolocalization of NLRP3 Inflammasome in Normal Murine Airway Epithelium and Changes following Induction of Ovalbumin-Induced Airway Inflammation

Tran, Hai B.; Lewis, Martin; Tan, Lor Wai; Lester, Susan; Baker, Leonie; Ng, Jia Yu; Hamilton‐Bruce, Monica Anne; Hill, Catherine; Koblar, Simon; Rischmueller, Maureen; Ruffin, Richard E.; Wormald, Peter John; Zalewski, Peter D.; Lang, Carol J.

doi:10.1155/2012/819176

Cited by 50 publications

(47 citation statements)

References 31 publications

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“…To investigate in which cell type the inflammasome activation occurred, immunohistological examinations were performed on lung tissue sections from mice exposed to 3 days of hypoxia and their normoxic controls. In lungs from mice breathing normal air, staining of NLRP3 and ASC was found mainly in the airway epithelium, in accordance with previous studies (48). Three days of hypoxic exposure, however, revealed infiltration of leukocytes, predominantly neutrophils shown by positive MPO staining, and also T cells shown by positive CD3 staining aggregating around pulmonary blood vessels (Fig.…”

Section: Resultssupporting

confidence: 91%

Absence of the inflammasome adaptor ASC reduces hypoxia-induced pulmonary hypertension in mice

Cero

Hillestad

Sjaastad

et al. 2015

American Journal of Physiology-Lung Cellular and Molecular Phys

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Pulmonary hypertension is a serious condition that can lead to premature death. The mechanisms involved are incompletely understood although a role for the immune system has been suggested. Inflammasomes are part of the innate immune system and consist of the effector caspase-1 and a receptor, where nucleotide-binding oligomerization domain-like receptor pyrin domain-containing 3 (NLRP3) is the best characterized and interacts with the adaptor protein apoptosis-associated speck-like protein containing a caspase-recruitment domain (ASC). To investigate whether ASC and NLRP3 inflammasome components are involved in hypoxiainduced pulmonary hypertension, we utilized mice deficient in ASC and NLRP3. Active caspase-1, IL-18, and IL-1␤, which are regulated by inflammasomes, were measured in lung homogenates in wild-type (WT), ASC Ϫ/Ϫ , and NLRP3 Ϫ/Ϫ mice, and phenotypical changes related to pulmonary hypertension and right ventricular remodeling were characterized after hypoxic exposure. Right ventricular systolic pressure (RVSP) of ASC Ϫ/Ϫ mice was significantly lower than in WT exposed to hypoxia (40.8 Ϯ 1.5 mmHg vs. 55.8 Ϯ 2.4 mmHg, P Ͻ 0.001), indicating a substantially reduced pulmonary hypertension in mice lacking ASC. Magnetic resonance imaging further supported these findings by demonstrating reduced right ventricular remodeling. RVSP of NLRP3Ϫ/Ϫ mice exposed to hypoxia was not significantly altered compared with WT hypoxia. Whereas hypoxia increased protein levels of caspase-1, IL-18, and IL-1␤ in WT and NLRP3 Ϫ/Ϫ mice, this response was absent in ASC Ϫ/Ϫ mice. Moreover, ASC Ϫ/Ϫ mice displayed reduced muscularization and collagen deposition around arteries. In conclusion, hypoxia-induced elevated right ventricular pressure and remodeling were attenuated in mice lacking the inflammasome adaptor protein ASC, suggesting that inflammasomes play an important role in the pathogenesis of pulmonary hypertension.inflammation; innate immunity; pulmonary vasculature PULMONARY HYPERTENSION can be a life-threatening condition leading to right-sided heart failure and premature death (5, 40). The pathogenesis of the various forms of pulmonary hypertension is not fully known, and insight into disease mechanisms is important for the development of improved treatment options for this severe condition. The role and importance of inflammation and immune activation in the development of pulmonary hypertension are not fully understood; however, inflammation has emerged as an important player. Clinically, increased circulating levels of IL-1␤ and IL-18 have been observed in patients with pulmonary arterial hypertension, indicating that inflammasomes can be activated in this condition (18,41). It is well known that innate immunity is activated in response to infection. However, in the last decade, new knowledge has emerged demonstrating that inflammatory pathways can also be activated as a result of cellular stress during sterile inflammation and that these inflammatory responses involve activation of inflammasomes (27). Inflammasome...

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Section: Resultssupporting

confidence: 91%

Absence of the inflammasome adaptor ASC reduces hypoxia-induced pulmonary hypertension in mice

Cero

Hillestad

Sjaastad

et al. 2015

American Journal of Physiology-Lung Cellular and Molecular Phys

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“…The auxiliary finding of inflammasome components in alveolar capillary endothelium leaves room for speculations about the contribution of vascular endothelium in alveolar tissue inflammation. These findings are supported by work done by Tran et al detecting NLRP3 inflammasome components in healthy and inflamed murine airway epithelium [26]. In contrast, NLRP3 mRNA could not be detected in human respiratory epithelia derived from bronchial brushing [30].…”

Section: Discussionsupporting

confidence: 75%

Nontypeable Haemophilus Influenzae Infection Upregulates the NLRP3 Inflammasome and Leads to Caspase-1-Dependent Secretion of Interleukin-1β — A Possible Pathway of Exacerbations in COPD

et al. 2013

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Rationale Nontypeable Haemophilus influenzae (NTHi) is the most common cause for bacterial exacerbations in chronic obstructive pulmonary disease (COPD). Recent investigations suggest the participation of the inflammasome in the pathomechanism of airway inflammation. The inflammasome is a cytosolic protein complex important for early inflammatory responses, by processing Interleukin-1β (IL-1β) to its active form.ObjectivesSince inflammasome activation has been described for a variety of inflammatory diseases, we investigated whether this pathway plays a role in NTHi infection of the airways.MethodsA murine macrophage cell line (RAW 264.7), human alveolar macrophages and human lung tissue (HLT) were stimulated with viable or non-viable NTHi and/or nigericin, a potassium ionophore. Secreted cytokines were measured with ELISA and participating proteins detected via Western Blot or immunohistochemistry.Measurements and Main ResultsWestern Blot analysis of cells and immunohistochemistry of lung tissue detected the inflammasome key components NLRP3 and caspase-1 after stimulation, leading to a significant induction of IL-1β expression (RAW: control at the lower detection limit vs. NTHi 505±111pg/ml, p<0.01). Inhibition of caspase-1 in human lung tissue led to a significant reduction of IL-1β and IL-18 levels (IL-1β: NTHi 24 h 17423±3198pg/ml vs. NTHi+Z-YVAD-FMK 6961±1751pg/ml, p<0.01).ConclusionOur data demonstrate the upregulation of the NRLP3-inflammasome during NTHi-induced inflammation in respiratory cells and tissues. Our findings concerning caspase-1 dependent IL-1β release suggest a role for the inflammasome in respiratory tract infections with NTHi which may be relevant for the pathogenesis of bacterial exacerbations in COPD.

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“…6A). The RNA levels for each gene were all within a fivefold range of the corresponding levels in other tissues (brain, lung, and liver) in which the NLRP3 inflammasome has been reported to exist (34)(35)(36) (Fig. 6B).…”

Section: Nlrp3 Inflammasome Pathway Gene Expression In Mouse Cochleamentioning

confidence: 65%

NLRP3 mutation and cochlear autoinflammation cause syndromic and nonsyndromic hearing loss DFNA34 responsive to anakinra therapy

Nakanishi

Kawashima

Kurima

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

119

116

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The NLRP3 inflammasome is an intracellular innate immune sensor that is expressed in immune cells, including monocytes and macrophages. Activation of the NLRP3 inflammasome leads to IL-1β secretion. Gain-of-function mutations of NLRP3 result in abnormal activation of the NLRP3 inflammasome, and cause the autosomal dominant systemic autoinflammatory disease spectrum, termed cryopyrin-associated periodic syndromes (CAPS). Here, we show that a missense mutation, p.Arg918Gln (c.2753G > A), of NLRP3 causes autosomal-dominant sensorineural hearing loss in two unrelated families. In family LMG446, hearing loss is accompanied by autoinflammatory signs and symptoms without serologic evidence of inflammation as part of an atypical CAPS phenotype and was reversed or improved by IL-1β blockade therapy. In family LMG113, hearing loss segregates without any other target-organ manifestations of CAPS. This observation led us to explore the possibility that resident macrophage/monocyte-like cells in the cochlea can mediate local autoinflammation via activation of the NLRP3 inflammasome. The NLRP3 inflammasome can indeed be activated in resident macrophage/monocyte-like cells in the mouse cochlea, resulting in secretion of IL-1β. This pathway could underlie treatable sensorineural hearing loss in DFNA34, CAPS, and possibly in a wide variety of hearing-loss disorders, such as sudden sensorineural hearing loss and Meniere’s disease that are elicited by pathogens and processes that stimulate innate immune responses within the cochlea.

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Immunolocalization of NLRP3 Inflammasome in Normal Murine Airway Epithelium and Changes following Induction of Ovalbumin-Induced Airway Inflammation

Cited by 50 publications

References 31 publications

Absence of the inflammasome adaptor ASC reduces hypoxia-induced pulmonary hypertension in mice

Absence of the inflammasome adaptor ASC reduces hypoxia-induced pulmonary hypertension in mice

Nontypeable Haemophilus Influenzae Infection Upregulates the NLRP3 Inflammasome and Leads to Caspase-1-Dependent Secretion of Interleukin-1β — A Possible Pathway of Exacerbations in COPD

NLRP3 mutation and cochlear autoinflammation cause syndromic and nonsyndromic hearing loss DFNA34 responsive to anakinra therapy

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