Paper - Review

DOI: 10.1101/cshperspect.a016287

Abstract

Inflammasome
→ are large cytosolic multi-protein complexes
→ 1⃣ response to detection of (infection- & stress-associated stimuli) 2⃣ lead → to the activation of (caspase-1-mediated inflammatory responses)
← including 1⃣ cleavage 2⃣ un-conventional secretion → (IL-1β & IL18)

Inflammasome activation
→ can be induced ← by a wide variety of (microbial pathogens)
→ mediates (host defense) → through 1⃣ activation of rapid (inflammatory responses) 2⃣ restriction of (pathogen replication)

The inflammasome
→ is a critical regulator ← of the commensal microbiota
← in the intestine

Inflammasomes
→ have been widely implicated
← in 1⃣ the development 2⃣ the progression ← of various chronic diseases

❗: discuss
→ the role of inflammasomes
← in 1⃣ infectious 2⃣ non-infectious inflammation

Introduction

Inflammasomes
→ are cytosolic molecular factories
← which consist of a sensor protein
← containing 1⃣ a caspase-recruitment domain 2⃣ the pro-inflammatory caspase 3⃣ caspase-1

Active (caspase-1 sub-sequently)
→ processes → the leaderless pro-inflammatory cytokines (1⃣ pro-IL-1β 2⃣ pro-IL-18)
→ are un-conventionally secreted ← on caspase-1 cleavage

Inflammasome-mediated (1⃣ processing 2⃣ secretion) ← of (1⃣ pro-IL-1β 2⃣ pro-IL-18)
→ enables → a rapid, tightly regulated and highly inducible → pro-inflammatory response

Inflammasome activation
→ can trigger → an inflammatory cell death ← dubbed pyroptosis
← which serves to blunt intra-cellular pathogen replication

NOD-like receptor family
→ was → the first family of sensor proteins ← discovered to form inflammasome
→ is comprised ← of 1⃣ 22 gene in human 2⃣ 33 genes in mice

NLRs
→ are classified & named
← according to their domain structure

This signaling domain
→ enables → the recruitment of caspase-1
← either 1⃣ directly, through a CARD 2⃣ indirectly, through a PYRIN domain

Additional families of genes
← that can nucleate the assembly of inflammasomes
→ 1⃣ the AIM2-like receptor (ALR) family 2⃣ the RIG-I-like receptor (RLR) family

Mechanisms of inflammasome activation

❓: in the inflammasome field
→ to the identities of (the specific signals)
← that lead to the assembly of the different 1⃣ NLRs 2⃣ ALRs 3⃣ RLRs
→ into active inflammasome complexes

∵ 1⃣ the expression patterns 2⃣ molecular structures 3⃣ stimuli
← which lead to activation of (the different inflammasomes)
→ are highly variable

The NLRP1 inflammasome

The NLRP1 inflammasome
→ was the first inflammasome → to be discovered

❓: NLRP1 inflammasome
→ could assemble spontaneously ← in cell lysates
❗: two natural ligands → for NLRP1
→ 1⃣ muramyl dipeptide (MDP) 2⃣ the Baciilus anthracis lethal toxin

These ligands
→ appear to be species-specific
∵ MDP can active human; but NOT mouse

NLRP1
→ shows species-specific differences
← at the genetic level

Humans
→ possess a single NLRP1 gene
← containing both 1⃣ PYRIN 2⃣ CARD domain

Mice
→ have a cluster of three homologous genes

The active fragment of (anthrax lethal toxin)
→ consist of (a zinc metalloproteinase)
← that gains access → to the cytosol of (infected host cells)

Nlrp1b
→ does NOT directly bind → anthrax toxin
Nlrp1b
→ sense the proteolytic activity ← of the toxin
∵ Cleavage of NLRP1b itself → proved sufficient → for activation of the receptor

This binding
→ induces → a conformational changes ← in NLRP1
← that allows binding of ATP

❓: 1⃣ to reveal → the precise mechanisms of (NLRP1 ligands) 2⃣ to identify → any additional NLRP1 ligands 3⃣ to elucidate → the functions of (mouse NLRP1a & NLRP1c)

The NLRP3 inflammasome

NLRP1
→ is expressed → at low levels ← in myeloid cells
NLRP1
→ can be induced ← by 1⃣ Toll-like receptor agonists 2⃣ inflammatory cytokines
← in an NF-κB-dependent manner

NLRP3-activating signals
→ induce → 1⃣ pathogen-associated molecular patterns (PAMPs) 2⃣ toxins ← from bacterial & viral & fungal & protozoan pathogens
∵ Many (diverse pathogens & pathogen-associated molecules) → can activate NLRP3

Three main models → for NLRP3 activation
→ have been proposed
→ 1⃣ the ion flux model 2⃣ the reactive oxygen species model 3⃣ the lysosome rupture model

Changes ← in cytosolic levels of (specific cations)
→ are proposed → to play a critical role ← in NLRP3 activation

Extra-cellular ATP
→ activates → the ATP-gated ion channel P2X7
→ triggers → rapid K+ efflux

The influenza M2 protein
→ triggers → export of H+ ions
→ from the Golgi complex → into the cytosol

Ion fluxes
→ activate → other inflammasomes
→ e.g. 1⃣ NLRP1b 2⃣ NLRC4

Ion fluxes
→ might only modulate → the threshold of caspase-1 activation
→ does NOT serve → as specific signals
← which trigger NLRP3 inflammasome activation

Oxidate stress (← in the form of ROS)
→ has been widely implicated
← in 1⃣ NLRP3 activation 2⃣ many NLRP3-activating stimuli
← including 1⃣ ATP 2⃣ alum 3⃣ uric acid 4⃣ Nigericin 5⃣ all induce ROS production

Intra-cellular ROS
← produced ← via the NADPH oxidase system
→ were thought → to activate NLRP3

ROS inhibitors
→ were shown → to inhibit NLRP3 actvation
∵ The role of ROS in NF-κB
→ mediate up-regulation of (1⃣ NLRP3 2⃣ pro-IL-1β transcription)

Increased amounts of ROS
→ were sensed ← by 1⃣ a complex of Thioredoxin 2⃣ Thioredoxin-interacting protein (TXNIP)

❗: An alternative role → for ROS
← in inflammasome activation

ROS-independent mitochondria-derived cardioliipin
→ was shown → to (bind & activate) NLRP3

1⃣ ROS 2⃣ mitochondria
→ play → a role
← in inflammasome 1⃣ formation 2⃣ activation

The NLRP3 inflammasome
→ was proposed → to sense (lysosomal rupture)
← during 1⃣ frustrated phagocytosis of crystalline 2⃣ large particulate molecules

Inhibitors (← of the lysosomal protease Cathepsin B)
→ reduce NLRP3 activation
∴ Proteolytic activity ← in the activation of NLRP3

❓: mechanism ← by which the NLRP3 inflammation
→ is activated

NLRP3 activation
→ was more complex
← with the discovery of (non-canonical inflammasome activation)

Non-canonical activation
→ involves → the activation of caspase-11
← by intra-cellular LPS released
← 1⃣ by rupture ← of bacteria-loaded phagolysosomes 2⃣ by bacteria ← that actively enter the cytosol

❗: caspase-11-dependent inflammasome activation
→ resulted ←from the realization ← that the caspase-1-deficient mice
❓: lack → a functional caspase-11
→ owing to a passenger mutation

The formation of (an inflammasome-like complex)
← containing a cytosolic LPS-receptor
→ precedes → caspase-11 activation

❓: Caspase-11 → interplays
← with the NLRP3 pathway

Activated caspase-11
← which initiated pyroptosis ← in a similar manner → as caspase-1
→ induces signals ← that are sub-sequently sensed ← by NLRP3

The NLRP6 and NLRP12 inflammasomes

NLRP6
→ is highly expressed
← in non-hematopoietic cells ← including 1⃣ epithelial cells 2⃣ goblet cells

NLRP6
→ plays → an important role
← in maintaining (intestinal homeostasis)

Co-expression ← of (1⃣ NLRP6 2⃣ ASC)
→ results ← in a synergistic activation of caspase-1-dependent cytokine processing
∴ NLRP6
→ might indeed form → an inflammasome

Alteration ← in the microbiota
→ associated ← with NLRP6 deficiency
∴ NLRP6 activation → might trigger IL-18 release

NLRP6
→ contributes → to mucus secretion
→ through the regulation of autophagy
← in 1⃣ IL-1β 2⃣ IL-18 independent manner

A negative regulator (← of 1⃣ NK-κB 2⃣ MAPK) signaling
→ lead to un-controlled pro-inflammatory response
← during bacterial challenge

❓: the role of NLRP6 ← in immune defense
❓: identification of the signals ← that lead to NLRP6 activation

NLRP12
→ possesses → several features
← that resemble NLRP6

NLRP12
→ plays → an important role
← in protecting ← against 1⃣ DSS-induced colitis 2⃣ AOM/DSS-induced colon cancer

NLRP12
→ appear → to maintain (intestinal homeostasis)
← by negatively regulating (inflammatory signaling pathways)
→ e.g. 1⃣ NF-κB 2⃣ MAPK

Forced co-expression ← of (NLRP12 & ASC)
→ results ← in 1⃣ synergistic activation of caspase-1 2⃣ secretion of IL-1β

❗: NLRP12 inflammasome
→ regulates → 1⃣ IL-18 2⃣ IL-1β production
❗: NLRP12-deficient mice
→ were more susceptible → to bacterial challenge

The NLRC4 inflammasome

NLRC4
→ is activated
← in response to many different (bacterial pathogens)

NLRC4
→ senses → 1⃣ bacterial flagellin 2⃣ structural component
← of the bacterial type III secretion system (T3SS)
← that are (injected & leaked) → into the host cell

These bacterial proteins
→ are directly bound
← by NLR-family apoptosis-inhibiting proteins (NAIPs)

NAIPs
→ interact ← with NLRC4
→ trigger → assembly of (the NLRC4 inflammasome complex)
→ release of (inflammatory cytokines & pyroptosis)

AIM2-like receptors and RIG-I-like receptors

Absent in melanoma 2 (AIM2) & ALRs
→ are member ← of the PYHIN family
← consist of protein ← that 1⃣ contain a PYRIN domain 2⃣ conserved DNA-binding domain hematopoietic IFN-inducible nuclear protein ← with 200-amino acids (HIN-200) domain

These proteins
→ bind (nucleic acids) & recruit ASC
→ to trigger → the formation of an inflammasome

AIM2
→ can form → an inflammasome
← whose assembly is stimulated
← by recognition of (cytosolic DNA) ← of 1⃣ bacterial 2⃣ viral origin 2⃣ self-DNA from apoptotic cells

❗: Crystal structure ← of AIM2
← complexed with DNA
→ have provided → particular insight → into the mechanism of AIM2 inflammasome activation

Binding of DNA
→ to the HIN domain of AIM2
→ results ← in 1⃣ a conformational changes 2⃣ AIM2 oligomerization
→ allows → for 1⃣ the recruitment of ASC & caspase-1 2⃣ inflammasome assembly

Most of these ALRs
← e.g. 1⃣ ALRs 2⃣ IFI16 3⃣ IFIX 4⃣ MNDA
→ remains poorly characterized

A number of (murine ALRs)
→ were found → to co-localize ← with ASC
→ trigger → IL-1β production
∴ They can form inflammasomes

Human IFI16
→ can form → an inflammasome
← in response to Kaposi's sarcoma
← associated herpes virus infection

Activation of IFI16
→ was found → to trigger massive pyroptosis of T-cells
→ is proposed → to be a main driver of (depletion of CD4 T-cells) ← during progression to AIDS

Inflammasomes in host defense against infections

Protection
← against invading micro-organisms
→ is likely → the primary function of (this arm of innate immune system)
∵ Considering → the main effect of inflammasome activation
→ is 1⃣ pyroptosis 2⃣ the secretion ← of (IL-1β & IL-18)

Inflammasome-activating microbes
→ can be divided → into three categories
→ 1⃣ intra-cellular pathogens 2⃣ extra-cellular pathoges 3⃣ passively invading commensals

All three types ← of inflammasome-activating microbes
→ are frequently found → at 1⃣ mucosal 2⃣ non-mucosal surfaces

Inflammasome proteins
→ are expressed
← at these surfaces
← by 1⃣ macrophages 2⃣ dendritic cells

Host-microbe interface
→ are increasingly recognized
→ to respond to invading microbes
← through inflammasome activation

Intestine

The intestinal tract
→ is continuously colonized ← with trillions of microbes
→ is continuously exposed → to new microbes ← that are ingested daily

The function of inflammasomes
→ has been clearly demonstrated
← in the context of (pathogenic bacterial infections)

Inflammasomes
→ initiate (protective responses)
→ 1⃣ Salmonella 2⃣ Citrobacter 3⃣ Clostridium

Recognition ← of these pathogens
∵ Several NLRs

NLRP3 & NLRC4
→ detect → S. typhimurium

IL-1β & IL-18
→ are important → for controlling S. typhimurium infection

C. rodentium infection
→ result ← in 1⃣ NLRP3 2⃣ NLRC4-dependent inflammatory response
← that limit 1⃣ bacterial burden 2⃣ tissue pathology

NLRP3 & NLRC4
→ sense C.rodentium
← in non-hematopoietic cells

❗: the localization of C. rodentium
→ NOT invade (host cells)
→ remains firmly attached → to intestinal epithelial cells

Other intestinal pathogens
← which were shown → to activate inflammasome
→ are 1⃣ C. difficile 2⃣ Yersinia 3⃣ Candida albicans

The importance ← of inflammasome activation
← in mediating bacterial control
→ highlighted ← by inflammasome-evasion strategies
∵ By the food-borne pathogen

DNA release
→ is kept ← at a minimum ← in wild-type bacteria
Flagellin
→ is strongly down-regulated
← during murine infection

Both 1⃣ S. typhimurium 2⃣ L. monocytogenes
→ are strongly attenuated
← when intra-cellular flagelline expression → is enforced
∵ the potent induction of (NLRC4-mediated pyroptosis)
∴ the potential of (this type of cell death) → to limit intra-celllular 1⃣ bacterial growth 2⃣ bacterial spread

S. typhimurium
→ was shown → to exploit this pathway
∵ caspase-11-deficient mice
→ showed decreased infection severity

Lung

A second major interface
← between 1⃣ the host 2⃣ the environment
→ is the lung

The surface of the lung
← in the upper airways
→ is continuously exposed
→ to a wide variety of (commensal & pathogenic) 1⃣ bacteria 2⃣ viruses 3⃣ fungi

Several different inflammasomes
→ detect → invading bacteria

The NLRC4 inflammasome
→ responds → to a number of flagellated bacteria
← including 1⃣ L. pneumoniae 2⃣ B. pseudomallei

Both 1⃣ the NLRP3 2⃣ AIM2 inflammasome
→ are proposed → to play a role
← during M. tuberculosis infection

The majority of inflammasome activation
→ helps → to (fight & resolve) bacterial lung infections
← through 1⃣ pyroptosis 2⃣ IL-1β 2⃣ IL-18 secretion

The role of inflammasomes
← in protection against (viral infections)
→ has been clearly demonstrated
∵ multiple studies

A virus
→ strongly activate NLRP3 ← in the lung
∴ Caspase-1-mediated inflammatory response
→ provide 1⃣ protection against 2⃣ healing after → infections

Several other lung viruses
→ induce NLRP3-mediated immune response
← including 1⃣ Rhinovirus 2⃣ human repository syncytial virus (RSV) 3⃣ Varicella-zoster virus

NLRP3 activation
→ occur ← mainly in macrophages
RIG-I was demonstrated
→ to sense influenza A virus
→ through detection of viral RNA ← in lung epithelial cells
∴ A protective type I interferon response

Several viral proteins
→ to be responsible → for NLRP3 activation

All of these proteins
→ target → membranes of intra-cellular organelles

1⃣ The influenza A M2 2⃣ Rhinovirus 2B ion channel protein
→ induce → ion fluxes
← from 1⃣ the Golgi 2⃣ ER

The viroporin SH protein
← from RSV
→ form pores ← in Golgi membranes
The influenza A protein PB1-F2
→ is incorporated ← in the membrane of phagelysosomes

These viruses
→ deliberately express → these inflammasome-activating proteins
Subsequent initiation
← of pro-inflammatory immune response
→ is usually detrimental → to the virus

The strength of (ligand selection) ← by NLRP3
∴ An evolutionary difficulty
→ to avoid NLRP3 activation

Some viruses
→ have likely developed mechanisms
→ to directly inhibit inflammasomes
→ to remain "under the radar" of the immune system

Many lung pathogens
→ can directly activate → the inflammasome
An additional pro-inflammatory stimulus
→ comes ← from host-derived DAMPs
← following infection-associated tissue damage

Sensing of (this type of damage)
→ is restricted → to the NLRP3 inflammasome
← which is activated ← in response to damage-associated molecules
← e.g. 1⃣ uric acid 2⃣ extra-cellular ATP 3⃣ serum amyloid A

Other examples of inflammasome activation in host-microbial interactions

Many other surface and cells
← that comes in contact with microbes
→ depend ← on inflammasome-mediated defense strategies

CD4 T-cells
→ are subject to HIV-induced IFI16 activation
→ which leads to 1⃣ caspase-1-mediated pyroptosis 2⃣ subsequent CD4 T-cell depletion

Inflammasomes and the commensal microbiota

❗: the inflammasome
→ to defense → against pathogenic microbes
❗: the inflammasome
→ may play a role ← in shaping the composition of (the intestinal microbiota)

Mice ← lacking NLRP6
→ harbored → an altered intestinal microbiota
← 1⃣ was characterized ← by the presence of Prevotellaceae species 2⃣ conferred increased susceptibility → to DSS-induced colitis

This alteration
← in 1⃣ microbial composition 2⃣ susceptibility → to colitis
→ was communicable → to wild-type mice
→ through 1⃣ co-housing 2⃣ flora transfer

A similar phenotype
→ was observed
← in mice (← lacking other inflammasome components & effectors)

∴ The assembly of (an NLRP6 inflammasome & secretion of IL-18)
→ are required → for maintenance of (intestinal hemostatis)
→ through (regulation of the composition of the microbiota)

The absence (← of the NLRP6 inflammasome)
→ leads → to (acquisition & expansion) ← of potentially (pathogenic members) of the microbiota

Inflammasome-dependent alterations
← in the microbiota
→ exacerbated → carcinogenesis
← in an inflammation-dependent model of (colon cancer)

❓: The precise mechanisms
← by which NLRP6 regulates → (microbial composition)
← in the intestine
→ remain unclear
∵ The stimuli (→ for NLRP6 activation) → are still completely unknown ❓

NLRP6 mice
→ displays → a defect in mucus secretion
← by goblet cells ← in the intestine
→ leads → to impaired mucosal defense

Defective mucus secretion ← in NLRP6 mice
→ favor → 1⃣ out-growth of (potentially pathogenic members) ← of the microbiota 2⃣ invasion ← of (the gut epithelial environment) ← by these organisms

❗: examination of (the role of the inflammasome)
← in regulation of the microbiota

Non-microbial inflammasome activators and disease

Chronic & low-grade inflammation
→ linked → to a variety of disease
← of both 1⃣ obvious 2⃣ non-obvious inflammatory nature

The triggers of such inflammation
→ can be either 1⃣ microbial derived 2⃣ non-microbital

Non-microbial triggers (← of inflammation)
→ can be separated ← into two categories
→ 1⃣ endogenous 2⃣ exogenous

Cryopyrin-associated periodic syndromes

The genesis of (the inflammasome field)
→ lies ← in the discovery ← which 1⃣ the hereditary diseases Familial Cold Auto-inflammtory syndrome (FCAS) 2⃣ Muckle-Wells syndrome
← by mutations in a single novel gene → containing a PYRIN domain
← which is now known as NLRP3

De novo mutations
← in NLRP3
→ cause → neonatal-onset multi-system inflammatory disease (NOMID)
→ chronic infantile neurological cutaneous and articular syndrome (CINCA)

These disorders
→ are considered → to be auto-inflammatory
← rather than auto-immune
∴ they are mediated primarily ← by cytokines of (the innate immune system)

Mice
← which engineered → to contain human mutant NLRP3
→ show a CAPS-like disorder

Macrophages
← from these mice
→ activate → 1⃣ caspase-1 2⃣ secrete IL-1β
→ in response → to microbial PAMPs ← without (the need for signal 2)

CAPS
→ results
← from the proclivity of NLRP3 mutants
← to assemble into (active inflammasomes)
∴ Normally insufficient → to trigger inflammasome activation

CAPS patients
→ are → highly responsive IL-1 blockade
∴ Dys-regulated production (← of IL-1β)
← by the NLRP3 inflammasome
→ is the major driver of pathology in CAPS

The role of IL-18
← in mice ← with CAPS-associated NLRP3 mutations
→ found that → 1⃣ IL-18 deficiency 2⃣ IL-1β deficiency 3⃣ dramatically ameliorated disease

Mice
← which lacking 1⃣ IL-1β 2⃣ IL-18
→ maintained → some residual caspase-1-dependent disease
∴ Cytokine-independent effects ← of the inflammasome

Gout

Gout
→ is a form of (inflammatory arthritis)
← that most commonly affects the joints ← at the base of the big toe
→ results ← from the pathological accumulation of (uric acid)
← which is the end product of (purine catabolism) & the subsequent (formation & deposition) ← uric acid crystals

Uric acid crystals
→ can activate → the NLRP3 inflammasome
→ trigger → IL-1β secretion
∴ (1⃣ Inflammasome activation 2⃣ IL-1β secretion) → may be a critical driver of (arthritis in gout)

IL-1 blockade
→ was subsequently found
→ to be a highly effective treatment → for gout

Osteoarthritis
← which is characterized ← by the degeneration of cartilage
→ has also been shown → to involve NLRP3 activation

Synovial (uric acid)
← correlated ← with synovial fluid 1⃣ IL-1β 2⃣ IL-18 ← in patients

∴ A detailed investigation of therapies
→ targeting 1⃣ the NLRP3 inflammasome 2⃣ its mediators
← in treating osteoarthritis
→ might be fruitful

Atherosclerosis

Atherosclerosis
→ is a thickening of (the artery wall)
← caused by (the accumulation & deposition) ← of 1⃣ cholesterol 2⃣ calcium 3⃣ cellcular debris
← in atherosclerotic plaques

∵ The accumulation of (cholesterol crystals)
← in atherosclerotic plaques
→ is a common feature of atherosclerosis
∵ Various crystals → are known to trigger
→ activation of the NLRP3 inflammasome

❗: cholesterol crystals
→ could trigger → NLRP3 inflammasome activation
❗: the inflammasome contributed → to the development of atherosclerosis
← in mice (← lacking the low-density lipoprotein receptor)
❗: Cholesterol crystals
→ were found → to trigger NLRP3 activation
← in human macrophages

∴ Inflammasome activation
← in response to cholesterol crystals
→ may be a critical early trigger of (inflammation)
← in atherosclerosis

The endocytic PRR CD36
→ is critical
→ for NLRP3 activation ← by oxidized LDL
→ but NOT in vitro-generated cholesterol crystals

Receptor-mediated uptake of LDL
→ is a primary event ← in crystal formation
∴ Inflammasome activation ← during atherosclerosis

❓: The important of (the NLRP3 inflammasome)
← in atherosclerosis
→ remain unclear
∵ NLRP3 deficient → had no effect
← on atherosclearosis development

1⃣ Caspase-1 2⃣ CD36 deficiency
→ reduce → the severity of atherosclerosis

Alzheimer's disease and amyotrophic lateral sclerosis

Mis-folded proteins aggregates
→ lead → to activation of (the NLRP3 inflammasome)
→ e.g. 1⃣ Alzheimer's disease 2⃣ ALS

AD
→ is a chronic neuro-degenerative disease
← that mainly affects cognitive functioning
← that is the most common cause of dementia

ALS
→ is a neuro-degenerative disease
← that results ← from the progressive death of (motor neurons)
← which eventually leads → to loss of control of (voluntary muscles)

Both 1⃣ AD 2⃣ ALS
→ are associated ← with the accumulation of (protein aggregates)

⭐: AD
The amyloid-β-protein (Aβ)
→ forms → extra-cellular plaques → that are though† to contribute → to disease development
⭐: ALS
Mutant forms of super-oxide dismutase 1 (SOD1)
→ that form toxic aggregates

Fibrilar Aβ
→ trigger → activation of the NLRP3 inflammasome
← in LPS-primed microglial cells

1⃣ Inflammasome activation 2⃣ IL-1β secretion
→ contribute → to the inflammatory response → to Aβ in the brain

ALS-linked mutant SOD1
→ trigger → inflammasome activation
← in microglia

Aggregates of (prion proteins)
→ activate → the NLRP3 inflammasome
∴ Aggregated proteins → may represent → a common class of (sterile triggers) ← of (inflammasome activation)

SNPs (← in NLRP1)
→ linked → to AD
∴ Multiple NLRs → may play → important roles
← in neuro-degenerative disorders

Inflammasome
→ may contribute → to the pathogenesis of neuro-degenerative disorders
← that are associated ← with the accumulation of (protein aggregates)
Inflammation
→ contribute → to disease (development & progression)

Metabolic syndrome and type 2 diabetes

The role of the inflammasome
← in 1⃣ metabolic syndrome 2⃣ type 2 diabetes (T2D)
→ can be separated ← into two major (mechanistic categories)
→ 1⃣ direct roles ← mediated by sensing (endogenous inflammasome activators) 2⃣ indirect roles ← mediated by inflammasome-associated alterations

Potential direct role ← of the inflammasome
← in metabolic syndrome

❗: alterations ← in the microbiota
→ contribute → to phenotypes
∵ Studies → did NOT (consider & control) → for potential effects ← of the microbiota

Mice
← deficient in 1⃣ NLRP3 2⃣ caspase-1 2⃣ ASC
→ are protected
← from high fat diet (HFD)-induced 1⃣ insulin resistance 2⃣ glucose intolerance 3⃣ inflammation 2⃣ obesity

Multiple potential mechanisms
← by which the NLRP3 inflammasome
→ may become activated ← in HFD-induced metabolic syndrome

The effected of NLRP3 deficiency
← on diabetes in mice
→ are partially pheno-copied ← by IL-1R deficiency

Inhibition of (NLRP3 inflammasome activation)
→ ameliorated → metabolic changes
← associated with HFD

Autoimmunity

1⃣ IL-1β 2⃣ IL-18
→ are critical
→ for the (initiation & control) ← of the adaptive immune response

The inflammasome
→ would also play → an important role
← in autoimmunity

Multiple NLRs
→ play important roles ← in auto-immune disease
∵ Studies ← in both (human & mice)

The clearest connection
← between 1⃣ auto-immunity 2⃣ the inflammasome
→ is the case of NLRP1

SNPs ← in NLRP1
→ have been linked → to 1⃣ vitiligo 2⃣ vitiligo-associated Addison's disease

❓: Confirmation of (the role of NLRP1)
← in autoimmunity ← in mice
→ has remained challenging
∵ Mice have three orthologs of NLRP1

❓: the mechanism
← by which NLRP1 SNPs influence autoimmunity
→ remains largely unclear

Autoimmunity-associated NLRP1 SNPs
→ may lead → to greater processing of (IL-1β)
← in response to inflammatory stimuli

❗: A few SNPs (← in NLRP3)
→ has been linked → to autoimmunity

NLRP3- & IL-1R-deficient mice
→ show reduced disease
← in a mouse model of (multiple sclerosis)

AIM2
→ play a role
← in 1⃣ autoimmunity 2⃣ auto-inflammation

AIM2 blockade
→ was found
→ to ameliorate development of auto-immunity
← in a model of lupus

Environmental inflammasome activators: allergens and particulates

❓: the role of the inflammasome
← in the allergic response
→ remains less well studied

Certain allergens
→ can trigger → inflammasome activation
House dust mite allergens
→ can trigger → NLRP3 inflammasome activation

❓: The role of the inflammasome
← in allergic response → to 1⃣ HDM 2⃣ venomes
→ remains unclear

Components of the inflammasome
→ were dispensable → for the allergic response

The inflammasome was critical
→ for the early inflammatory response
→ to envenomation

NLRP3 → was found
→ to be dispensable
→ for the allergic response → to intra-nasal HDM allergen

The inflammasome
→ has linked → to allergic contact dermatitis (ACD)
∵ Contact hyper-sensitivity

Particulate environmental substances
→ have been shown → to activate the inflammasome

Both 1⃣ silica 2⃣ asbestos
→ can trigger → activation of (the NLRP3 inflammasome)

The inflammasome
→ plays → a critical role
← in the progressive pulmonary fibrotic disorders
← 1⃣ silicosis 2⃣ asbestosis

Necrosis
← triggered ← by 1⃣ pressure disruption 2⃣ hypoxia 3⃣ complement lysis 4⃣ chemically induced epithelial cell injury
→ lead → to activation of (the NLRP3 inflammasome)

Perspective and future prospects

The major beneficial roles ← of the inflammasome
→ is → to 1⃣ sense microbial infection 2⃣ mediate a rapid program ← of (host defense)
→ through 1⃣ the immediate secretion of pre-made cytokines 2⃣ triggering of cell death

These response
→ are (highly efficient)
← in fighting off (infectious agents) ← of various origins

Many non-microbial activators
← of the inflammasome
→ are known
∴ Inflammasome → can function
← as sensors of non-microbial signals
← 1⃣ sterile mediators of (membrane damage) 2⃣ cellular stress

These non-microbial triggers ← of the inflammasome
→ have been studied
∵ their pathological roles ← in disease

Current studies
→ support → the idea
← that inflammasome activation
← by non-infectious triggers is largely un-intentional

Non-infectious triggers ← of the inflammasome
→ mediate → activation through NLRP3

❓: whether other NLRs can sense
→ non-microbial sense of physiological stress

Many NLRs
← whose respective roles ← in 1⃣ host defense 2⃣ physiology
→ are just beginning → to be appreciated

The major hurdles
→ to overcome
→ seems → to be identifying (the activating signals)

These NLRs
→ do NOT respond → to the expected signals
→ do NOT engage → 1⃣ traditional inflammasome effector responses 2⃣ trigger inflammasome activation ← in unexpected cell types

The effects of (inflammasome activation)
→ have focused
← on the roles of 1⃣ IL-1β 2⃣ IL-18 3⃣ pyroptosis

❗: potential 1⃣ cytokine- 2⃣ pyroptosis-independent roles
→ for the inflammasome

---