NLRP3, aluminum adjuvants, & silica: insulin resistance, neuroinflammation, demyelination

[Guest guest]

*Questions suggested by the abstracts*:

A. Should a person with metabolic syndrome and likely insulin resistance

avoid vaccinations with vaccines containing alum adjuvants?

B. Should a child with autism and anti-MBP titer (eg, 8) avoid

vaccinations with vaccines containing alum adjuvants?

C. If too many of a person's regularly ingested supplements contain

silica (eg 9-10), is he or she risking NLRP3 activation and thereby

augmenting tendencies toward insulin resistance, demyelination?

*//*

Fatty acid-induced NLRP3-ASC inflammasome activation interferes with

insulin signaling (1).

NLRP3 has other acronyms and participates in " the immunostimulatory

properties of aluminium adjuvants " (2).

NLRP3 participates in demyelination (3).

NLRP3 is induced by silica (4, see also 5-7).

/*

References:*/

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. Crucial role for the Nalp3 inflammasome in the immunostimulatory

properties of aluminium adjuvants.

<http://www.ncbi.nlm.nih.gov/pubmed/18496530>

Eisenbarth SC, Colegio OR, O'Connor W, Sutterwala FS, Flavell RA.

Nature. 2008 Jun 19;453(7198):1122-6. Epub 2008 May 21.

Aluminium adjuvants, typically referred to as 'alum', are the most

commonly used adjuvants in human and animal vaccines worldwide,

yet the mechanism underlying the stimulation of the

immune system by alum remains unknown. Toll-like receptors

are critical in sensing infections and are therefore common targets

of various adjuvants used in immunological studies. Although

alum is known to induce the production of proinflammatory cytokines

in vitro, it has been repeatedly demonstrated that alum does

not require intact Toll-like receptor signalling to activate the

immune system1,2. Here we show that aluminium adjuvants

activate an intracellular innate immune response system called

the Nalp3 (also known as cryopyrin, CIAS1 or */NLRP3/*) inflammasome...

3. The inflammasome sensor, NLRP3, regulates CNS inflammation and

demyelination via caspase-1 and interleukin-18.

<http://www.ncbi.nlm.nih.gov/pubmed/21106820>

Jha S, Srivastava SY, Brickey WJ, Iocca H, Toews A, on JP, Chen

VS, Gris D, Matsushima GK, Ting JP.

J Neurosci. 2010 Nov 24;30(47):15811-20.

Inflammation is increasingly recognized as an important contributor to a

host of CNS disorders; however, its regulation in the brain is not well

delineated. Nucleotide-binding domain, leucine-rich repeat, pyrin domain

containing 3 (NLRP3) is a key component of the inflammasome complex,

which also includes ASC (apoptotic speck-containing protein with a card)

and procaspase-1. Inflammasome formation can be triggered by membrane

P2X(7)R engagement leading to cleavage-induced maturation of caspase-1

and interleukin-1? (IL-1?)/IL-18. This work shows that expression of the

Nlrp3 gene was increased >100-fold in a cuprizone-induced demyelination

and neuroinflammation model. Mice lacking the Nlrp3 gene (Nlrp3(-/-))

exhibited delayed neuroinflammation, demyelination, and oligodendrocyte

loss in this model. These mice also showed reduced demyelination in the

experimental autoimmune encephalomyelitis model of neuroinflammation.

This outcome is also observed for casp1(-/-) and IL-18(-/-) mice,

whereas IL-1?(-/-) mice were indistinguishable from wild-type controls,

indicating that Nlrp3-mediated function is through caspase-1 and IL-18.

Additional analyses revealed that, unlike the IL-1?(-/-) mice, which

have been previously shown to show delayed remyelination, Nlrp3(-/-)

mice did not exhibit delayed remyelination. Interestingly, IL-18(-/-)

mice showed enhanced remyelination, thus providing a possible

compensatory mechanism for the lack of a remyelination defect in

Nlrp3(-/-) mice. These results suggest that NLRP3 plays an important

role in a model of multiple sclerosis by exacerbating CNS inflammation,

and this is partly mediated by caspase-1 and IL-18. Additionally, the

therapeutic inhibition of IL-18 might decrease demyelination but enhance

remyelination, which has broad implications for demyelinating diseases.

4. The effect of surface modification of amorphous silica particles on

NLRP3 inflammasome mediated IL-1beta production, ROS production and

endosomal rupture. <http://www.ncbi.nlm.nih.gov/pubmed/20561679>

Morishige T, Yoshioka Y, Inakura H, Tanabe A, Yao X, Narimatsu S, Monobe

Y, Imazawa T, Tsunoda S, Tsutsumi Y, Mukai Y, Okada N, Nakagawa S.

Biomaterials. 2010 Sep;31(26):6833-42.

5. Cutting edge: TNF-alpha mediates sensitization to ATP and silica via

the NLRP3 inflammasome in the absence of microbial stimulation.

<http://www.ncbi.nlm.nih.gov/pubmed/19542372>

Franchi L, Eigenbrod T, Núñez G.

J Immunol. 2009 Jul 15;183(2):792-6.

6. Silica crystals and aluminum salts activate the NALP3 inflammasome

through phagosomal destabilization.

<http://www.ncbi.nlm.nih.gov/pubmed/18604214>

Hornung V, Bauernfeind F, Halle A, Samstad EO, Kono H, Rock KL,

Fitzgerald KA, Latz E.

Nat Immunol. 2008 Aug;9(8):847-56.

7. Innate immune activation through Nalp3 inflammasome sensing of

asbestos and silica. <http://www.ncbi.nlm.nih.gov/pubmed/18403674>

Dostert C, Pétrilli V, Van Bruggen R, Steele C, Mossman BT, Tschopp J.

Science. 2008 May 2;320(5876):674-7.

8. Brain-derived neurotrophic factor and autoantibodies to neural

antigens in sera of children with autistic spectrum disorders,

Landau-Kleffner syndrome, and epilepsy.

<http://www.ncbi.nlm.nih.gov/pubmed/16181614>

Connolly AM, Chez M, Streif EM, Keeling RM, Golumbek PT, Kwon JM,

Riviello JJ, RG, Neuman RJ, Deuel RM.

Biol Psychiatry. 2006 Feb 15;59(4):354-63.

9. Silicate nephrolithiasis after ingestion of supplements containing

silica dioxide. <http://www.ncbi.nlm.nih.gov/pubmed/19100669>

Flythe JE, Rueda JF, Riscoe MK, Watnick S.

Am J Kidney Dis. 2009 Jul;54(1):127-30.

10. discussions via google:

" dioxide in supplements " silica silicon

more:

Towards an understanding of the adjuvant action of aluminium.

<http://www.ncbi.nlm.nih.gov/pubmed/19247370>

Marrack P, McKee AS, Munks MW.

Nat Rev Immunol. 2009 Apr;9(4):287-93.

Alum induces innate immune responses through macrophage and mast cell

sensors, but these sensors are not required for alum to act as an

adjuvant for specific immunity.

<http://www.ncbi.nlm.nih.gov/pubmed/19734227>

McKee AS, Munks MW, MacLeod MK, Fleenor CJ, Van Rooijen N, Kappler JW,

Marrack P.

J Immunol. 2009 Oct 1;183(7):4403-14.

Silica Crystals and Aluminum Salts Regulate the Production of

Prostaglandin in Macrophages via NALP3 Inflammasome-Independent

Mechanisms. <http://www.ncbi.nlm.nih.gov/pubmed/21497116>

Kuroda E, Ishii KJ, Uematsu S, Ohata K, Coban C, Akira S, Aritake K,

Urade Y, Morimoto Y.

Immunity. 2011 Apr 22;34(4):514-26.

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 salts.

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.

Mitochondria: Sovereign of inflammation?

<http://www.ncbi.nlm.nih.gov/pubmed/21469137>

Tschopp J.

Eur J Immunol. 2011 May;41(5):1196-202. doi: 10.1002/eji.201141436.

NLRP3 inflammasome-dependent inflammatory responses are triggered by a

variety of signals of host danger, including infection, tissue damage

and metabolic dysregulation. How these diverse activators cause

inflammasome activation is poorly understood. Recent data suggest that

the mitochondria integrate these distinct signals and relay this

information to the NLRP3 inflammasome. Dysfunctional mitochondria

generate ROS, which is required for inflammasome activation. On the

contrary, the NLRP3 inflammasome is negatively regulated by autophagy,

which is a catabolic process that removes damaged or otherwise

dysfunctional organelles, including mitochondria. In addition to the

processing and secretion of pro-inflammatory cytokines such as IL-1?,

NLRP3 inflammasome activation also influences cellular metabolic

pathways such as glycolysis and lipogenesis. Mapping the connections

between mitochondria, metabolism and inflammation is of great interest,

as malfunctioning of this network is associated with many chronic

inflammatory diseases.

Cholesterol crystals activate the NLRP3 inflammasome in human

macrophages: a novel link between cholesterol metabolism and

inflammation. <http://www.ncbi.nlm.nih.gov/pubmed/20668705>

Rajamäki K, Lappalainen J, Oörni K, Välimäki E, Matikainen S, Kovanen

PT, Eklund KK.

PLoS One. 2010 Jul 23;5(7):e11765.

Acetaminophen-induced hepatotoxicity in mice is dependent on Tlr9 and

the Nalp3 inflammasome. <http://www.ncbi.nlm.nih.gov/pubmed/19164858>

Imaeda AB, Watanabe A, Sohail MA, Mahmood S, Mohamadnejad M, Sutterwala

FS, Flavell RA, Mehal WZ.

J Clin Invest. 2009 Feb;119(2):305-14. doi: 10.1172/JCI35958. Epub 2009

Jan 26.

Hepatocyte death results in a sterile inflammatory response that

amplifies the initial insult and increases overall tissue injury. One

important example of this type of injury is acetaminophen-induced liver

injury, in which the initial toxic injury is followed by innate immune

activation. Using mice deficient in Tlr9 and the inflammasome components

Nalp3 (NACHT, LRR, and pyrin domain-containing protein 3), ASC

(apoptosis-associated speck-like protein containing a CARD), and

caspase-1, we have identified a nonredundant role for Tlr9 and the Nalp3

inflammasome in acetaminophen-induced liver injury. We have shown that

acetaminophen treatment results in hepatocyte death and that free DNA

released from apoptotic hepatocytes activates Tlr9. This triggers a

signaling cascade that increases transcription of the genes encoding

pro-IL-1beta and pro-IL-18 in sinusoidal endothelial cells. By

activating caspase-1, the enzyme responsible for generating mature

IL-1beta and IL-18 from pro-IL-1beta and pro-IL-18, respectively, the

Nalp3 inflammasome plays a crucial role in the second step of

proinflammatory cytokine activation following acetaminophen-induced

liver injury. Tlr9 antagonists and aspirin reduced mortality from

acetaminophen hepatotoxicity. The protective effect of aspirin on

acetaminophen-induced liver injury was due to downregulation of

proinflammatory cytokines, rather than inhibition of platelet

degranulation or COX-1 inhibition. In summary, we have identified a

2-signal requirement (Tlr9 and the Nalp3 inflammasome) for

acetaminophen-induced hepatotoxicity and some potential therapeutic

approaches.