alum, asthma, NLRP3

[Guest guest]

An endogenous molecule known as the inflammasome participates in immune

activation (here <http://en.wikipedia.org/wiki/Inflammasome>). Nod-like

receptors NLRP3 (aka nalp3 or cias1 or cryopyrin) participate in the

activation of inflammasomes and are implicated in asthma (eg, 1-4).

Aluminum as a vaccinal adjuvant (alum) induces expression of NLRP3 (eg,

5-8). Are alum injections a contributing factor in the increased

prevalence of asthma (eg, 9)?

*//*

1. The role of the NLRP3 Inflammasome in the pathogenesis of airway

disease. <http://www.ncbi.nlm.nih.gov/pubmed/21421008>

Birrell MA, Eltom S.

Pharmacol Ther. 2011 Jun;130(3):364-70.

The incidences of respiratory diseases like asthma and Chronic

Obstructive Pulmonary Disease (COPD) are increasing dramatically.

Significantly, there are currently no treatments that can slow or

prevent the relentless progression of COPD; and a sub-population of

asthmatics are resistant to available therapies. What is more, currently

prescribed medication has only minimal effect on the symptoms suffered

in these patient groups. There is therefore an urgent need to develop

effective drugs to treat these diseases. Whilst asthma and COPD are

thought to be distinct diseases, it is currently believed that the

pathogenesis of both is driven by the chronic inflammation present in

the airways of these patients. It is thus hypothesised that if the

inflammation could be attenuated, disease development would be slowed

and symptoms reduced. It is therefore paramount to determine the

pathways driving/propagating the inflammation. Recently there has been a

growing body of evidence to suggest that the multimeric protein complex

known as the Inflammasome may play key roles in the inflammation

observed in respiratory diseases. The aim of this review is to discuss

the role of the NLRP3 Inflammasome, and its associated inflammatory

mediators (IL-1? and IL-18), in the pathogenesis of asthma and COPD.

2. Associations of functional NLRP3 polymorphisms with susceptibility to

food-induced anaphylaxis and aspirin-induced asthma.

<http://www.ncbi.nlm.nih.gov/pubmed/19767079>

Hitomi Y, Ebisawa M, Tomikawa M, Imai T, Komata T, Hirota T, Harada M,

Sakashita M, Suzuki Y, Shimojo N, Kohno Y, Fujita K, Miyatake A, Doi S,

Enomoto T, Taniguchi M, Higashi N, Nakamura Y, Tamari M.

J Allergy Clin Immunol. 2009 Oct;124(4):779-85.e6.

Our results indicate that the NLRP3 SNPs might play an important role in

the development of food-induced anaphylaxis and AIA in a

gain-of-function manner. Further research on the NLRP3 inflammasome will

contribute to the development of novel diagnostic and therapeutic

methods for food-induced anaphylaxis and AIA.

3. Nod-like receptors in innate immunity and inflammatory diseases.

<http://www.ncbi.nlm.nih.gov/pubmed/18038361>

Carneiro LA, Travassos LH, Girardin SE.

Ann Med. 2007;39(8):581-93.

Over the past few years the field of innate immunity has undergone a

revolution with the discovery of pattern recognition molecules (PRM) and

their role in microbe detection. Among these molecules, the Nod-like

receptors (NLRs) have emerged as key microbial sensors that participate

in the global immune responses to pathogens and contribute to the

resolution of infections. This growing group of proteins is divided into

subfamilies with basis in their different signaling domains. Prominent

among them are Nod1, Nod2, Nalp3 [aka NLRP3], Ipaf, and Naip that have

been shown to play important roles against intracellular bacteria.

Furthermore, mutations in the genes that encode these proteins have been

associated with complex inflammatory disorders including Crohn's

disease, asthma, familial cold urticaria, Muckle-Wells syndrome, and

Blau syndrome. In this review we will present the current knowledge on

the role of these proteins in immunity and inflammatory diseases.

4. NLRP3 inflammasome is required in murine asthma in the absence of

aluminum adjuvant. <http://www.ncbi.nlm.nih.gov/pubmed/21443539>

Besnard AG, Guillou N, Tschopp J, Erard F, Couillin I, Iwakura Y,

Quesniaux V, Ryffel B, Togbe D.

Allergy. 2011 Mar 28. doi: 10.1111/j.1398-9995.2011.02586.x.

Background: Inflammasome activation with the production of IL-1?

received substantial attention recently in inflammatory diseases.

However, the role of inflammasome in the pathogenesis of asthma is not

clear. Using an adjuvant-free model of allergic lung inflammation

induced by ovalbumin (OVA), we investigated the role of NLRP3

inflammasome and related it to IL-1R1 signaling pathway. Methods:

Allergic lung inflammation induced by OVA was evaluated in vivo in mice

deficient in NLRP3 inflammasome, IL-1R1, IL-1? or IL-1?. Eosinophil

recruitment, Th2 cytokine, and chemokine levels were determined in

bronchoalveolar lavage fluid, lung homogenates, and mediastinal lymph

node cells ex vivo. Results: Allergic airway inflammation depends on

NLRP3 inflammasome activation. Dendritic cell recruitment into lymph

nodes, Th2 lymphocyte activation in the lung and secretion of Th2

cytokines and chemokines are reduced in the absence of NLRP3. Absence of

NLRP3 and IL-1? is associated with reduced expression of other

proinflammatory cytokines such as IL-5, IL-13, IL-33, and thymic stromal

lymphopoietin. Furthermore, the critical role of IL-1R1 signaling in

allergic inflammation is confirmed in IL-1R1-, IL-1?-, and

IL-1?-deficient mice. Conclusion: NLRP3 inflammasome activation leading

to IL-1 production is critical for the induction of a Th2 inflammatory

allergic response.

5. Mechanism of action of clinically approved adjuvants.

<http://www.ncbi.nlm.nih.gov/pubmed/19246182>

Lambrecht BN, Kool M, Willart MA, Hammad H.

Curr Opin Immunol. 2009 Feb;21(1):23-9.

Aluminum-containing adjuvants continue to be the most widely used

adjuvants for human use. In the last year a major breakthrough has been

the realization that alum adjuvant triggers an ancient pathway of innate

recognition of crystals in monocytes and triggers them to become

immunogenic dendritic cells, nature's adjuvant. This recognition can

occur directly, via the triggering of the NALP3 [aka NLRp3] inflammasome

by alum crystals, or indirectly through release of the endogenous danger

signal uric acid. It is also clear now that adjuvants trigger the

stromal cells at the site of injection, leading to the necessary

chemokines that attract the innate immune cells to the site of

injection. How exactly these pathways interact remains to be determined.

6. Novel cellular and molecular mechanisms of induction of immune

responses by aluminum adjuvants.

<http://www.ncbi.nlm.nih.gov/pubmed/19439372>

Aimanianda V, Haensler J, Lacroix-Desmazes S, Kaveri SV, Bayry J.

Trends Pharmacol Sci. 2009 Jun;30(6):287-95.

....Aluminum adjuvants activate the nucleotide-binding domain and

leucine-rich-repeat-containing gene family pyrin-domain-containing 3

(known as NLRP3 or NALP3) inflammasome to activate caspase-1 and to

induce proinflammatory cytokines interleukin (IL)-1beta and IL-18 by

innate cells. Aluminum adjuvants activate NLRP3 by multiple mechanisms

such as by causing damage and rupture of the phagolysosomes, generating

reactive oxygen species, inducing K(+) efflux and via release from

injured tissues of molecules that constitute danger-associated molecular

patterns (DAMPs) such as uric acid and ATP. These novel cellular and

molecular mechanisms of aluminum salts are likely to influence how we

design effective and safe adjuvants in the future.

7. The inflammasome and alum-mediated adjuvanticity.

<http://www.ncbi.nlm.nih.gov/pubmed/20948671>

Kang SJ, Locksley RM.

F1000 Biol Rep. 2009 Feb 24;1. pii: 15

Recent reports have implicated the NLRP3-associated inflammasome in the

adjuvanticity of alum. Here, we summarize the major findings...

8. Getting closer to the dirty little secret.

<http://www.ncbi.nlm.nih.gov/pubmed/21511178>

Pelka K, Latz E.

Immunity. 2011 Apr 22;34(4):455-8.

The molecular mechanism behind alum adjuvanticity is probably the oldest

secret of immunology. In this issue of Immunity, Kuroda et al. (2011)

and Kool et al. (2011) identify NLRP3 inflammasome-independent signaling

to be crucial for the Th2 cell response induced by aluminum salt

9. MMWR:

Vital Signs: Asthma Prevalence, Disease Characteristics, and

Self-Management Education --- United States, 2001--2009

<http://www.cdc.gov/mmwr/preview/mmwrhtml/mm60e0503a1.htm?s_cid=mm60e0503a1_w>