alum & NLRP3: implications for metabolic syndrome becoming diabetes

[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 impair insulin signaling (eg, 1-3; see

also 4-5). Aluminum as a vaccinal adjuvant (alum) induces expression of

NLRP3 (eg, 6-9). Are alum injections a contributing factor in the

increased prevalence of or exacerbations of insulin resistance,

metabolic syndrome, and diabetes 2)? Are alum injections

contra-indicated for individuals with metabolic syndrome?

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/*1. Fatty acid-induced NLRP3-ASC inflammasome activation interferes

with insulin signaling. <http://www.ncbi.nlm.nih.gov/pubmed/21478880>

Wen H, Gris D, Lei Y, Jha S, Zhang L, Huang MT, Brickey WJ, Ting JP.

Nat Immunol. 2011 May;12(5):408-15.

High-fat diet (HFD) and inflammation are key contributors to insulin

resistance and type 2 diabetes (T2D). Interleukin (IL)-1? plays a role

in insulin resistance, yet how IL-1? is induced by the fatty acids in an

HFD, and how this alters insulin signaling, is unclear. We show that the

saturated fatty acid palmitate, but not unsaturated oleate, induces the

activation of the NLRP3-ASC inflammasome, causing caspase-1, IL-1? and

IL-18 production. This pathway involves mitochondrial reactive oxygen

species and the AMP-activated protein kinase and unc-51-like kinase-1

(ULK1) autophagy signaling cascade. Inflammasome activation in

hematopoietic cells impairs insulin signaling in several target tissues

to reduce glucose tolerance and insulin sensitivity. Furthermore, IL-1?

affects insulin sensitivity through tumor necrosis factor-independent

and dependent pathways. These findings provide insights into the

association of inflammation, diet and T2D.

/

/2. Dampening insulin signaling by an NLRP3 'meta-flammasome'.

<http://www.ncbi.nlm.nih.gov/pubmed/21502990>

Choi AM, Nakahira K.

Nat Immunol. 2011 May;12(5):379-80

3. Targeting IL-1beta in disease; the expanding role of NLRP3

inflammasome. <http://www.ncbi.nlm.nih.gov/pubmed/20493414>

Mitroulis I, Skendros P, Ritis K.

Eur J Intern Med. 2010 Jun;21(3):157-63.

NLRP3 inflammasome activation and IL-1beta secretion have recently

emerged as a central mechanism in the pathogenesis of disease.

Genetically defined syndromes like cryopyrin-associated periodic

syndromes (CAPS, cryopyrinopathies) and familial Mediterranean fever

(FMF) or diseases associated with NLRP3 activation by danger signals

like gout, pseudogout, Alzheimer's disease or type 2 diabetes are

included in this group of diseases. The contribution of anakinra, a

recombinant, nonglycosylated human IL-1 receptor antagonist, in both the

identification and treatment of such syndromes was considerable.

Recently, rilonacept, a long-acting IL-1 receptor fusion protein, and

canakinumab, a fully humanized anti-IL-1beta monoclonal antibody, have

been developed, with the intention to further extent IL-1beta inhibition

treatment strategies to a broader spectrum of disorders beyond the

characterized autoinflammatory syndromes, offering a more favorable

administration profile. On the other hand, the developed caspase-1

inhibitors, even though effective in experimental models, were not

proven efficient in the treatment of inflammatory diseases.

4. Inflammasome-mediated autoinflammatory disorders.

<http://www.ncbi.nlm.nih.gov/pubmed/20861596>

SP, Cassel SL.

Postgrad Med. 2010 Sep;122(5):125-33.

The nucleotide-binding domain leucine-rich repeat containing (NLR)

family of receptors are members of the innate immune system, and have a

critical role in host defense. These molecules are key to driving

inflammatory responses to abnormal cellular conditions. Many NLRs serve

this role on activation by forming a multiprotein complex called an

inflammasome. The inflammasome drives the processing and release of

cytokines, such as the proinflammatory cytokines interleukin (IL)-1? and

IL-18. Recently, the important function of NLR molecules in

autoinflammatory disorders has been recognized, in part through the

identification of the role of IL-1? in the pathogenesis of several

autoinflammatory diseases. Cryopyrin-associated periodic syndromes were

the first autoinflammatory disorders found to be directly mediated by

dysfunctional inflammasome activation. This finding has subsequently led

to studies in both murine models and humans that have revealed several

other inflammatory conditions associated with activation of

NLR-containing inflammasomes. Understanding the molecular

pathophysiology of these autoinflammatory disorders has further guided

the successful development of targeted therapy against IL-1. In this

review, we provide an overview of the inflammasomes and describe the

important role they play in the development and manifestation of

autoinflammatory diseases.

5. Current Status of Understanding the Pathogenesis and Management of

Patients With NOMID/CINCA. <http://www.ncbi.nlm.nih.gov/pubmed/21538043>

Goldbach-Mansky R.

Curr Rheumatol Rep. 2011 May 3.

Neonatal-onset multisystem inflammatory disease (NOMID)/chronic

infantile neurologic, cutaneous, and arthritis (CINCA) syndrome is the

most severe clinical phenotype in the spectrum of cryopyrin-

(NLRP3/NALP3) associated periodic syndromes (CAPS). The study of

patients with NOMID/CINCA has been instrumental in characterizing the

extent of organ-specific inflammatory manifestations and damage that can

occur with chronic interleukin (IL)-1? overproduction. Mutations in

CIAS1/NLRP3 lead to constitutive activation of the " NLRP3 inflammasome, "

an intracellular platform that processes and secretes increased amounts

of IL-1?. The pivotal role of IL-1? in NOMID/CINCA has been demonstrated

in several clinical studies using IL-1-blocking agents that lead to

rapid resolution of the inflammatory disease manifestations. NOMID/CINCA

is a monogenic autoinflammatory syndrome; and the discovery of the role

of IL-1 in NOMID has led to the exploration in the role of IL-1 in other

disorders including gout and Type II diabetes. The inflammation in

NOMID/CINCA is continuous with intermittent flares, and organ

manifestations encompus the central nervous system, eye, inner ear, and

bones. This review discusses updates on the pathogenesis of NOMID/CAPS,

emerging long term-outcome data regarding IL-1-blocking agents that have

influenced our considerations for optimal treatment, and a monitoring

approach tailored to the patient's disease severity and organ

manifestations.

6. 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.

7. 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.

8. 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...

9. 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