NLRP3 inflammasome: A therapeutic option for kidney disease?

El inflamasoma NLRP3: ¿Es realmente una opción terapéutica para la enfermedad renal?

Neudo Buelvas-Jiménez Raibel J. Suárez-Useche José R. Vielma-Guevara About the authors

ABSTRACT

Objective

To determine if considering inflammasome NLRP3 as a treatment option for kidney disease is possible.

Methods

Literature review related to NLRP3 inflammasome structure, biological function and relationship with renal disease and others (hypertension, diabetes, gout, atherosclerosis, amyloidosis, Alzheimer's disease); the systematic review was made searching in the databases PubMed and SciELO for the following terms: "The NLRP3 inflammasome therapeutic for kidney disease", "NLRP3 nflammasome in kidney disease" in PubMed, and "Inflammasome" for Scielo.

Results

146 documents were found, althoughonly 34 matched the working hypothesis concerning the NLRP3 inflammasome as a central component of various diseases in humans, with potential therapeutic use. The NLRP3 inflammasome is responsible for the maturation of inflammatory pro-interleukin IL-1 β and IL-18, which can be triggered by aggregated or crystalline materials (particles), and by various microorganisms and toxins derived from these; however, the way how activation mechanisms work is not completely clear.

Conclusions

Research on new therapies that focus on removing or inhibiting inflammasome components, both individually and together, is proposed.

Key Words:
Inflammation; inflammasomes; chronic renal diseases; hypertension; interleukins (source: MeHS, NLM)

RESUMEN

Objetivo

Determinar si el inflamasoma NLRP3 puede considerarse como opción de tratamiento para la enfermedad renal.

Métodos

Con el fin de encontrar bibliografía relacionada con la estructura del inflamasoma NLRP3, su función biológica y su relación con la enfermedad renal y otras (hipertensión, diabetes, gota, aterosclerosis, amiloidosis, enfermedad de Alzheimer), se realizó una revisión sistemática en dos bases de datos (PubMed y SciELO) con los términos: "NLRP3 inflammasome therapeutic for kidney disease" y "NLRP3 inflammasome in kidney disease" en PubMed, e "Iinflammasome" en SciELO.

Resultados

Se encontró un total de 146 documentos, de los cuales solo 34 concuerdan con la hipótesis de trabajo desarrollada con relación al inflamasoma NLRP3 como componente central de diversas enfermedades en seres humanos y con potencial uso terapéutico. El inflamasoma NLRP3 es responsable de la maduración de la interleucina inflamatoria pro-IL-1 β y IL-18, l cual puede darse por causa de materiales agregados o cristalinos (partículas), y por diversos microorganismos y toxinas derivadas de los mismos; sin embargo, los mecanismos de activación de este proceso siguen sin ser claros en la actualidad.

Conclusiones

Se propone estudiar nuevas terapias que se centren en la eliminación o inhibición de los componentes inflamasoma, de manera individual y conjunta.

Palabras Clave:
Inflamación; inflamasomas; insuficiencia renal crónica; interleucinas; hipertensión (fuente: DeCS, BIREME)

A qualitative systematic review of documents was performed, only in English, in the PubMed and Scielo databases, without using any quality assessment model for the treatment of the information found. Of the 146 works selected, only 42 were related to the assembly and activation of the NLRP3 inflammasome: 27 were about pathophysiological mechanisms of renal damage and NLRP3 inflammasome, 12 about oxidative stress, 9 about autoimmunity, and 56 about other diseases; the search was restricted to the period 2002-2015. 34 documents related directly to the working hypothesis -activation or assembly NLRP3 inflammasome as a therapeutic target in kidney disease, hypertension, diabetes, and related diseases- were included.

Inflammation is a control program preserved evolutionarily and derived from host defenses to deal with infections and tissue damage. Innate immune cells such as macrophages, mast cells and dendritic cells, as well as circulating leukocytes, are able to recognize the invasion by microorganisms and cell damage through a set of receptor proteins called pattern recognition receptors (PRRs) 11. Rodríguez-Iturbe B, Franco M, Tapia E, Quiroz Y, Johnson RJ. Renal inflammation, autoimmunity and salt-sensitive hypertension. Clin Exp Pharmacol Physiol. 2012; 39 (1): 96-103. http://www.ncbi.nlm.nih.gov/pubmed/21251049.
http://www.ncbi.nlm.nih.gov/pubmed/21251...

2. Lorenz G, Darisipudi MN, Anders HJ. Canonical and non-canonical effects of the NLRP3 inflammasome in kidney inflammation and fibrosis. Nephrol Dial Transplant. 2014; 29 (1): 41-48. http://www.ncbi.nlm.nih.gov/pubmed/24026244.
http://www.ncbi.nlm.nih.gov/pubmed/24026...

3. Pons H, Ferrebuz A, Quiroz Y, Romero-Vásquez F, Parra G, Johnson RJ, et al. Immune reactivity to heat shock protein 70 expressed in the kidney is cause of salt-sensitive hypertension. Am J Physiol Renal Physiol. 2013; 304 (3): F289-299. http://www.ncbi.nlm.nih.gov/pubmed/23097471.
http://www.ncbi.nlm.nih.gov/pubmed/23097...

4. Newton K, Dixit VM. Signaling in Innate Immunity and Inflammation. Cold Spring Harb Perspect Biol. 2012; 4 (3): 1-19. http://www.ncbi.nlm.nih.gov/pubmed/22296764.
http://www.ncbi.nlm.nih.gov/pubmed/22296...

5. Suárez R, Buelvas N. El inflamasoma: mecanismos de activación. Invest Clin. 2015; 56 (1): 74-99. http://www.ncbi.nlm.nih.gov/pubmed/25920188.
http://www.ncbi.nlm.nih.gov/pubmed/25920...
-66. Buelvas-Jiménez N, Suárez-Useche R. Regulación del inflamasoma: bioquímica y más allá de ella. IATREIA. 2015; 28 (2): 170-180. http://www.scielo.org.co/pdf/iat/v28n2/v28n2a07.pdf
http://www.scielo.org.co/pdf/iat/v28n2/v...
. PRRs are plasma membrane-anchored or intracellular receptors that detect microbe-associated molecular patterns (MAMPs) which derive from microorganisms, and damage-associated molecular patterns (DAMPs) which derive from endogenous danger signals 77. Franchi L, Kamada N, Nakamura Y, Burberry A, Kuffa P, Suzuki S, et al. NLRC4-driven interleukin-1β production discriminates between pathogenic and commensal bacteria and promotes host intestinal defense. Nat Immunol. 2012; 13 (5): 449-456. http://www.ncbi.nlm.nih.gov/pubmed/22484733.
http://www.ncbi.nlm.nih.gov/pubmed/22484...
.

Activation and assembling of PRRs in large supramolecular complexes (e.g. inflammasomes) initiate the signaling cascades that allow the release of cytokines, chemokines, as well as the recruitment of immune cells into the tissue damaged 88. Esser N, Legrand S, Piette J, Scheen AJ, Paquot N. Inflammation as a link between obesity, metabolic syndrome and type 2 diabetes. Diabetes Res Clin Pract. 2014; 105 (2): 141-150. http://www.ncbi.nlm.nih.gov/pubmed/24798950.
http://www.ncbi.nlm.nih.gov/pubmed/24798...
-99. Andersen K, Eltrich N, Lichtnekert J, Anders HJ, Vielhauer V. The NLRP3/ASC inflammasome promotes T-cell-dependent immune complex glomerulonephritis by canonical and noncanonical mechanisms. Kidney Int. 2014; 86 (5): 965-978. http://www.ncbi.nlm.nih.gov/pubmed/24805106.
http://www.ncbi.nlm.nih.gov/pubmed/24805...
.

The NLRP3 inflammasome is the best characterized of these multiprotein complexes; it contains leucine-rich repeats (LRR) in its N-terminal end, a highly conserved central nucleotide-binding domain (NACHT by its acronym, also known as nucleotide oligomerization domain or NOD), and a PYD domain in its C-terminus end 1010. Vajjhala PR, Mirams RE, Hill JM. Multiple binding sites on the pyrin domain of ASC protein allow self-association and interaction with NLRP3 protein. J Biol Chem. 2012; 287 (50): 41732-41743. http://www.ncbi.nlm.nih.gov/pubmed/23066025.
http://www.ncbi.nlm.nih.gov/pubmed/23066...
-1111. Halff E, Diebolder C, Versteeg M, Schouten A, Brondijk H, Huizinga E. Formation and structure of a NAIP5-NLRC4 inflammasome induced by direct interactions with conserved n- and c-terminal regions of flagellin. J Biol Chem. 2012; 287 (46): 38460-38472. http://www.ncbi.nlm.nih.gov/pubmed/23012363.
http://www.ncbi.nlm.nih.gov/pubmed/23012...
. This receptor is the most important PRR involved in the assembly and activation of inflammasome 1212. Tschopp J, Martinon F, Burns K. NALPs: a novel protein family involved in inflammation. Nat Rev Mol Cell Biol. 2003; 4 (2): 95-104. http://www.ncbi.nlm.nih.gov/pubmed/12563287.
http://www.ncbi.nlm.nih.gov/pubmed/12563...
.

After activation, NLRP3 protein oligomerizes and interacts with two additional proteins, ASC protein (which contains a caspase recruitment domain and a pyrene domain) and procaspase-1. As a result of this interaction, caspase-1 protein is activated 1313. Py BF, Kim MS, Vakifahmetoglu-Norberg H, Yuan J. Deubiquitination of NLRP3 by BRCC3 critically regulates inflammasome activity. Mol Cell. 2013; 49 (2): 331-338. http://www.ncbi.nlm.nih.gov/pubmed/23246432.
http://www.ncbi.nlm.nih.gov/pubmed/23246...
. The processing of caspase-1 is essential for proteolytic cleavage and secretion of inflammatory pro-interleucins 1β (pro-IL1β) and 18 (proIL-18). Under certain conditions, activation of caspase-1 generates pyroptosis, a form of inflammatory cell death similar to apoptosis and necrosis 1414. Anders HJ, Muruve DA. The Inflammasomes in Kidney Disease. J Am Soc Nephrol. 2011; 22 (6): 1007-1018. http://www.ncbi.nlm.nih.gov/pubmed/21566058.
http://www.ncbi.nlm.nih.gov/pubmed/21566...
. One relevant aspect of NLRP3 inflammasome activation is that signaling and the mechanisms for activation and assembly by various exogenous and endogenous noxious stimuli are not fully elucidated yet.

On the other hand, the defective activation and disproportionate action of the NLRP3 inflammasome relates to the etiology of various diseases and autoinflammatory syndromes such as hereditary periodic fever syndrome, the Muckle-Wells syndrome 1515. Caorsi R, Lepore L, Zulian F, Alessio M, Stabile A, Insalaco A, et al. The schedule of administration of canakinumab in cryopyrin associated periodic syndrome is driven by the phenotype severity rather than the age. Arthritis Res Ther. 2013; 15 (1):1-8. http://www.ncbi.nlm.nih.gov/pubmed/23442610.
http://www.ncbi.nlm.nih.gov/pubmed/23442...
, septic shock induced by lipopolysaccharide 1616. Kang SJ, Wang S, Kuida K, Yuan J. Distinct downstream pathways of caspase-11 in regulating apoptosis and cytokine maturation during septic schock response. Cell Death Differ. 2002; 9 (10): 1115-1125. http://www.ncbi.nlm.nih.gov/pubmed/12232800.
http://www.ncbi.nlm.nih.gov/pubmed/12232...
, gout 1717. Ghaemi-Oskouie F, Shi Y. The role of uric acid as an endogenous danger signal in immunity and inflammation. Curr Rheumatol Rep. 2011; 13 (2): 160-166. http://www.ncbi.nlm.nih.gov/pubmed/21234729.
http://www.ncbi.nlm.nih.gov/pubmed/21234...
, type 2 diabetes 1818. Lee H, Kim J, Kim H, Shong M, Ku B, Jo E. Upregulated NLRP3 inflammasome activation in patients with type 2 diabetes. Diabetes. 2013; 62 (1): 194-204. http://www.ncbi.nlm.nih.gov/pubmed/23086037.
http://www.ncbi.nlm.nih.gov/pubmed/23086...
, metabolic syndrome 1919. De Nardo D, Latz E. NLRP3 inflammasomes link inflammation and metabolic disease. Trends Immunol. 2011; 32 (8): 373-379. http://www.ncbi.nlm.nih.gov/pubmed/21733753.
http://www.ncbi.nlm.nih.gov/pubmed/21733...
, hypertension 22. Lorenz G, Darisipudi MN, Anders HJ. Canonical and non-canonical effects of the NLRP3 inflammasome in kidney inflammation and fibrosis. Nephrol Dial Transplant. 2014; 29 (1): 41-48. http://www.ncbi.nlm.nih.gov/pubmed/24026244.
http://www.ncbi.nlm.nih.gov/pubmed/24026...
, atherosclerosis 1919. De Nardo D, Latz E. NLRP3 inflammasomes link inflammation and metabolic disease. Trends Immunol. 2011; 32 (8): 373-379. http://www.ncbi.nlm.nih.gov/pubmed/21733753.
http://www.ncbi.nlm.nih.gov/pubmed/21733...
, amyloidosis 2020. Strowig T, Henao J, Elinav E, Flavell R. Inflammasomes in health and disease. Nature. 2012; 481 (7381): 278-286. http://www.ncbi.nlm.nih.gov/pubmed/22258606.
http://www.ncbi.nlm.nih.gov/pubmed/22258...
and Alzheimer's disease 2121. Di Bona D, Plaia A, Vasto S, Cavallone L, Lescai F, Franceschi C, et al. Association between the interleukin-1beta polymorphisms and Alzheimer’s disease: a systematic review and meta-analysis. Brain Res Rev. 2008; 59 (1): 155-163. http://www.ncbi.nlm.nih.gov/pubmed/22356904.
http://www.ncbi.nlm.nih.gov/pubmed/22356...
.

Hypotheses

One important question in nephrology is whether kidney diseases are related directly or indirectly to the NLRP3 inflammasome and, if so, how and where the problem begins, since many authors conclude that renal pathologies have, as common characteristics, the extravasation and infiltration of inflammatory cells, as well as the expression and secretion of the cytokines IL-1β and IL-18 in the kidney tissue 1414. Anders HJ, Muruve DA. The Inflammasomes in Kidney Disease. J Am Soc Nephrol. 2011; 22 (6): 1007-1018. http://www.ncbi.nlm.nih.gov/pubmed/21566058.
http://www.ncbi.nlm.nih.gov/pubmed/21566...
. Bakker (2014) pointed out that chronic kidney disease is irreversible and is characterized by tubulointerstitial inflammation, fibrosis and glomerulosclerosis, which are associated with hyperuricemia; it is further known that the latter causes NLRP3 inflammasome activation 2222. Bakker PJ, Butter LM, Kors L, Teske GJ, Aten J, Sutterwala FS, et al. Nlrp3 is a key modulator of diet-induced nephropathy and renal cholesterol accumulation. Kidney Int. 2014; 85 (5): 1112-1122. http://www.ncbi.nlm.nih.gov/pubmed/24352154.
http://www.ncbi.nlm.nih.gov/pubmed/24352...
.

Our research group has proposed that the expression of heat shock proteins (HSPs) and the concentration of oxygen and nitrogen reactive species (ROS and RNS respectively) are increased in the kidneys of patients 33. Pons H, Ferrebuz A, Quiroz Y, Romero-Vásquez F, Parra G, Johnson RJ, et al. Immune reactivity to heat shock protein 70 expressed in the kidney is cause of salt-sensitive hypertension. Am J Physiol Renal Physiol. 2013; 304 (3): F289-299. http://www.ncbi.nlm.nih.gov/pubmed/23097471.
http://www.ncbi.nlm.nih.gov/pubmed/23097...
,2323. Rodríguez-Iturbe B, Pons H, Quiroz Y, Lanaspa MA, Johnson RJ. Autoimmunity in the pathogenesis of hypertension. Nature Rev Nephrol. 2014; 10 (1): 56-62. http://www.ncbi.nlm.nih.gov/pubmed/24247285.
http://www.ncbi.nlm.nih.gov/pubmed/24247...
-2424. Tschopp J, Schroder K. NLRP3 inflammasome activation: the convergence of multiple signaling pathways on ROS production? Nature Rev Immunol. 2010; 10 (3): 210-215. http://www.ncbi.nlm.nih.gov/pubmed/20168318.
http://www.ncbi.nlm.nih.gov/pubmed/20168...
. On the other hand, the monosodium urate crystals resulting from hyperuricemia are effectors of the NLRP3 activation 1717. Ghaemi-Oskouie F, Shi Y. The role of uric acid as an endogenous danger signal in immunity and inflammation. Curr Rheumatol Rep. 2011; 13 (2): 160-166. http://www.ncbi.nlm.nih.gov/pubmed/21234729.
http://www.ncbi.nlm.nih.gov/pubmed/21234...
.

Researchers have speculated about the differences in signaling mechanisms caused by the NLRP3 inflammasome to direct infiltration of inflammatory cells and epithelial-mesenchymal transformation in the renal tubule. This process is associated with tubular atrophy and progressive interstitial fibrosis in kidney tissue, which apparently runs NLRP3 by stimulation with TGF-β in different renal compartments 22. Lorenz G, Darisipudi MN, Anders HJ. Canonical and non-canonical effects of the NLRP3 inflammasome in kidney inflammation and fibrosis. Nephrol Dial Transplant. 2014; 29 (1): 41-48. http://www.ncbi.nlm.nih.gov/pubmed/24026244.
http://www.ncbi.nlm.nih.gov/pubmed/24026...
.

Wree (2014) previously showed that the NLRP3 inflammasome can be expressed constitutively and can also be the cause of damage to the liver 2525. Wree A, Eguchi A, McGeough MD, Pena CA, Johnson CD, Canbay A, et al. NLRP3 Inflammasome activation results in hepatocyte pyroptosis, liver inflammation, and fibrosis in mice. Hepatology. 2014; 59 (3): 898-910. http://www.ncbi.nlm.nih.gov/pubmed/23813842.
http://www.ncbi.nlm.nih.gov/pubmed/23813...
. This activation results in abnormal development of cellular stress and, therefore, will generate a positive feedback, which will increase the degree of the inflammatory process; this raises the question of whether this constitutive expression could occur in other organs. It is necessary to devise new strategies to address, from different perspectives, the study of inflammasomes, including genetic and epigenetic analysis of each case, to direct appropriate anti-inflammatory therapies in a personalized manner.

Another important function of NLRP3, besides acting as a sensor of cell damage and activating an inflammatory response in the cell cytoplasm, is its dual subcellular location; it is located in the cytosol and is also associated with other organelles (e.g. the nucleus), even in differential locations of T cell subsets. A possible explanation for the difference in the activity of TH1 and TH2 cells could be the subcellular localization of NLRP3. Cytoplasmic localization of NLRP3 might promote inflammasome assembly, while nuclear location might favor the transcriptional function of the inflammasome 2626. Subramanian N, Natarajan K, Clatworthy MR, Wang Z, Germain RN. The adapter MAVS promotes NLRP3 mitochondrial localization and inflammasome activation. Cell. 2013; 153 (2): 348-361. http://www.ncbi.nlm.nih.gov/pubmed/23582325.
http://www.ncbi.nlm.nih.gov/pubmed/23582...
, which is reflected on the results of the work of Bruchard (2727. Bruchard M, Rebé C, Derangère V, Togbé D, Ryffel B, Boidot R, et al. The receptor NLRP3 is a transcriptional regulator of TH2 differentiation. Nat immunol. 2015; 16 (8): 859-870. http://www.ncbi.nlm.nih.gov/pubmed/26098997.
http://www.ncbi.nlm.nih.gov/pubmed/26098...
, who found that NLRP3 expression in CD4+ T cells, specifically, supported type 2 T helper (TH2) transcriptional programs in a cell-intrinsic manner.

NLRP3 positively regulated a TH2 program, although this was not the case of the inflammasome adaptor ASC nor of caspase-1. In TH2 cells, NLRP3 bounded the Il4 promoter and transactivated it along with the transcription factor IRF4. Nlrp3-deficient TH2 cells supported melanoma tumor growth in an IL-4-dependent manner and also promoted asthma-like symptoms. These results demonstrate the ability of NLRP3 to act as a key transcription factor in TH2 differentiation.

Together, these observations on the effects and actions of the NLRP3 inflammasome on innate immunity and tissue damage make possible to see that the role of this complex goes beyond a simple proteolytic processing, proinflammatory cytokines activation, transcriptional functions, and pyroptosis induction.

One of the conclusions after our review of the literature on renal diseases is that basic and applied research in the renal field in relation to inflammasome should now focus on whether the therapeutic approach or the pharmacological inhibition of NLRP3 are sufficient for treatment, even for reversing kidney problems, in order to be closer to ensure a better quality of life for patients.

Table 1 shows the five compounds that have the ability of inhibiting NLRP3 inflammasome activation by directly interfering with the inflammasome or this assembly. There are four exogenous (synthetic) compounds that inhibit inflammasome-NLRP3, namely, Bay 11-782 2828. Juliana C, Fernandes-Alnemri T, Wu J, Datta P, Solorzano L, Yu JW, et al. Anti-inflammatory compounds parthenolide and Bay 11-7082 are direct inhibitors of the inflammasome. J Biol Chem. 2010; 285 (13): 9792-9802. http://www.ncbi.nlm.nih.gov/pubmed/20093358.
http://www.ncbi.nlm.nih.gov/pubmed/20093...
, 3, 4-methylenedioxy-β-nitrostyrene (MNS) 2929. He Y, Varadarajan S, Muñoz-Planillo R, Burberry A, Nakamura Y, Núñez G. 3, 4-methylenedioxy-β-nitrostyrene inhibits NLRP3 inflammasome activation by blocking assembly of the inflammasome. J Biol Chem . 2014; 289 (2):1142-1150. http://www.ncbi.nlm.nih.gov/pubmed/24265316.
http://www.ncbi.nlm.nih.gov/pubmed/24265...
, MCC 950 3434. Levy M, Thaiss CA, Elinav E. Taming the inflammasome. Nat Med. 2015; 21 (3): 213-215. http://www.ncbi.nlm.nih.gov/pubmed/25742454.
http://www.ncbi.nlm.nih.gov/pubmed/25742...
and dimethyl sulfoxide (DMSO) 3030. Ahn H, Kim J, Jeung EB, Lee GS. Dimethyl sulfoxide inhibits NLRP3 inflammasome activation. Immunobiology. 2014; 219 (4): 315-322. http://www.ncbi.nlm.nih.gov/pubmed/24380723.
http://www.ncbi.nlm.nih.gov/pubmed/24380...
, although these agents have limited potency and are non-specific.

Table 1
Inhibitory compounds of the NLRP3 inflammasome

In this sense, MCC950 (small-molecule inhibitor of the NLRP3 inflammasome) blocked canonical and non-canonical NLRP3 activation at nanomolar concentrations. The half maximal inhibitory concentration (IC50) of MCC950 was approximately 7.5 nM in mouse bone marrow-derived macrophages, which is similar to human monocyte-derived macrophages (IC50 = 8.1 nM). The secretion of LPS-dependent tumor necrosis factor-α was not impaired by MCC950, which demonstrates that the inhibition of IL-1β secretion was specific. MCC950 inhibited specifically the activation of NLRP3, but not of the AIM2, NLRC4 or NLRP1 inflammasomes. MCC950 reduced interleukin-1β (IL-1β) production in vivo, and attenuated the severity of experimental autoimmune encephalomyelitis 3131. Coll RC, Robertson AA, Chae JJ, Higgins SC, Muñoz-Planillo R, Inserra MC, et al. A small-molecule inhibitor of the NLRP3 inflammasome for the treatment of inflammatory diseases. Nat Med. 2015; 21 (3): 248-255. http://www.ncbi.nlm.nih.gov/pubmed/25686105.
http://www.ncbi.nlm.nih.gov/pubmed/25686...
.

Renal inflammation, fibrosis and elevated blood pressure induced by 1K/DOCA/salt treatment in mice depend on inflammasome activity, stressing the inflammasome/IL-1β pathway as a potential therapeutic target in hypertension. Additionally, MCC950 (at a concentration of 10 mg kg-1d-1, s.c.) reversed hypertension in the animals treated with 1K/DOCA/salt 3232. Krishnan SM, Dowling JK, Ling YH, Diep H, Chan CT, Ferens D, et al. Inflammasome activity is essential for one kidney/deoxycorticosterone acetate/salt-induced hypertension in mice. Br J Pharmacol. 2015; 173 (4): 752-765. http://www.ncbi.nlm.nih.gov/pubmed/26103560.
http://www.ncbi.nlm.nih.gov/pubmed/26103...
.

Other endogenous compounds block the activation of NLRP3 inflammasome. Youm 3333. Youm YH, Nguyen KY, Grant RW, Goldberg EL, Bodogai M, Kim D, et al. The ketone metabolite β-hydroxybutyrate blocks NLRP3 inflammasome-mediated inflammatory disease. Nat Med. 2015; 21 (3): 263-269. http://www.ncbi.nlm.nih.gov/pubmed/25686106.
http://www.ncbi.nlm.nih.gov/pubmed/25686...
reports that one of such compounds is ketone body, β-hydroxybutyrate (BHB) -but not the structurally related acetoacetate or butyrate-, which specifically inhibits NLRP3 inflammasome activation and downstream cytokine production by numerous known NLRP3 activators in mouse bone marrow-derived macrophages and human monocytes in vitro.

Dose-dependently BHB inhibited 1L-1β and IL-18 secretion, without significantly affecting tumor necrosis factor (TNF-α) production, as demonstrated in culture supernatants of human monocytes stimulated with LPS (1 µg/mL) for 4 hours, in the presence of an increasing concentration of BHB (1, 10 and 20 mM). At millimolar concentrations BHB blocks the NLRP3 inflammasome without undergoing oxidation in the tricarboxylic acid cycle, and independently of uncoupling protein-2 (UCP2), sirtuin-2 (SIRT2), G protein-coupled receptor GPR109A, or hydrocaboxylic acid receptor 2 (HCAR2). When administered in complex to mice at physiological concentrations with nanolipogens that improve bioavailability, β-hydroxybutyrate blocked NLRP3 inflammasome activation in response to monosodium ureate (MSU) crystals, which is the causative agent of gout 3333. Youm YH, Nguyen KY, Grant RW, Goldberg EL, Bodogai M, Kim D, et al. The ketone metabolite β-hydroxybutyrate blocks NLRP3 inflammasome-mediated inflammatory disease. Nat Med. 2015; 21 (3): 263-269. http://www.ncbi.nlm.nih.gov/pubmed/25686106.
http://www.ncbi.nlm.nih.gov/pubmed/25686...
-3434. Levy M, Thaiss CA, Elinav E. Taming the inflammasome. Nat Med. 2015; 21 (3): 213-215. http://www.ncbi.nlm.nih.gov/pubmed/25742454.
http://www.ncbi.nlm.nih.gov/pubmed/25742...
.

Up to date, the only clinically available therapeutics for NLRP3-driven autoinflammatory diseases are antibodies targeting IL-1β signaling, which are not specific for NLRP3 activity. Unlike anakinra, rilonacept, and canakinumab, both MCC950 (synthetic) and BHB (endogenous) act as specific inhibitors of NLRP3 and do not affect Toll-like receptors signaling (TLR) or other inflammasome-forming NLRs 3434. Levy M, Thaiss CA, Elinav E. Taming the inflammasome. Nat Med. 2015; 21 (3): 213-215. http://www.ncbi.nlm.nih.gov/pubmed/25742454.
http://www.ncbi.nlm.nih.gov/pubmed/25742...
.

DISCUSSION

NLRP3 inflammasome activation results in the release of pro-inflammatory interleukins. Several authors have demonstrated the presence of these interleukins in organs with inflammasome hyperactivation caused by intrinsic or extrinsic damage, for which kidney disease is not the exception; however, inflammasome activation has not been proved to be the cause in the light of an experimental model. Therefore, studying new therapies that focus on removing or inhibiting inflammasome components, both individually and together, is proposed in order to develop the hypothesis raised here.

The involvement of inflammasome in human disease has incited efforts to identify potent and specific ways to interfere with NLRP3 activation in the context of auto-inflammatory diseases, including other diseases such as obesity, diabetes and hypertension.

REFERENCES

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  • Author contributions
    NBJ, RSU and JRV participated equally in the conception, design, drafting and review of the manuscript submitted to arbitration.

Publication Dates

  • Publication in this collection
    Jan-Feb 2017

History

  • Received
    27 Nov 2015
  • Reviewed
    10 Aug 2015
  • Accepted
    08 Dec 2016
Instituto de Salud Publica, Facultad de Medicina - Universidad Nacional de Colombia Bogotá - DF - Colombia
E-mail: revistasp_fmbog@unal.edu.co