Korean J Physiol Pharmacol.  2018 Jan;22(1):1-15. 10.4196/kjpp.2018.22.1.1.

Role of inflammasomes in inflammatory autoimmune rheumatic diseases

• Yi YS

• KMID: 2398550
• DOI: http://doi.org/10.4196/kjpp.2018.22.1.1

Abstract

Inflammasomes are intracellular multiprotein complexes that coordinate anti-pathogenic host defense during inflammatory responses in myeloid cells, especially macrophages. Inflammasome activation leads to activation of caspase-1, resulting in the induction of pyroptosis and the secretion of pro-inflammatory cytokines including interleukin (IL)-1β and IL-18. Although the inflammatory response is an innate host defense mechanism, chronic inflammation is the main cause of rheumatic diseases, such as rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), ankylosing spondylitis (AS), and Sjögren's syndrome (SS). Since rheumatic diseases are inflammatory/autoimmune disorders, it is reasonable to hypothesize that inflammasomes activated during the inflammatory response play a pivotal role in development and progression of these diseases. Indeed, previous studies have provided important observations that inflammasomes are actively involved in the pathogenesis of inflammatory/autoimmune rheumatic diseases. In this review, we summarize the current knowledge on several types of inflammasomes during macrophage-mediated inflammatory responses and discuss recent research regarding the role of inflammasomes in the pathogenesis of inflammatory/autoimmune rheumatic diseases. This avenue of research could provide new insights for the development of promising therapeutics to treat inflammatory/autoimmune rheumatic diseases.

Keyword

Autoimmunity; Inflammasome; Inflammation; Macrophage; Rheumatic diseases

MeSH Terms

Arthritis, Rheumatoid
Autoimmunity
Cytokines
Inflammasomes*
Inflammation
Interleukin-18
Interleukins
Lupus Erythematosus, Systemic
Macrophages
Multiprotein Complexes
Myeloid Cells
Pyroptosis
Rheumatic Diseases*
Spondylitis, Ankylosing
Cytokines
Inflammasomes
Interleukin-18
Interleukins
Multiprotein Complexes

Figure

• 

  Fig. 1 Structures and compositions of canonical (A-D) and non-canonical (E) inflammasomes.(A) NLRP1 directly interacts with pro-caspase-1 through their CARD motifs. (B) NLPR3 interacts with pro-caspase-1 through a bipartite adaptor molecule, ASC. NLRP3 interacts with ASC through their PYD motifs, and ASC interacts with pro-caspase-1 through their CARD motifs. (C) NLRC4 directly interacts with pro-caspase-1 through their CARD motifs. (D) AIM2 interacts with pro-caspase-1 through a bipartite adaptor molecule, ASC. AIM2 interacts with ASC through their PYD motifs, and ASC interacts with pro-caspase-1 through their CARD motifs. (E) Pro-caspase-4/5 in a human and pro-caspase-11 in a mouse directly interact with the lipid A moiety of LPS through their CARD motifs. LRR, Leucine-rich repeat; NRL, nucleotide-binding oligomerization domain-like receptor; caspase, cysteine-aspartic protease; CARD, caspase recruit domain; NACHT, nucleotide binding and oligomerization domain; FIIND, function to find domain; AIM2, absent in melanoma 2; PYD, pyrin domain; HIN, hematopoietic interferon-inducible nuclear proteins; LPS, lipopolysaccharide. *Autocatalytic cleavage.

• 

  Fig. 2 Graphical summary of the roles of inflammasomes in inflammatory/autoimmune rheumatic diseases.(A) The SNPs and gene expression of NLRP1 and NLRP3, and intracellular NLRP3 level are increased in RA compared to healthy normal control. The activation of NLRP1 and NLRP3 inflammasomes by the assembly with ASC and pro-caspase-1 is induced in RA compared to healthy normal control. In contrast, in a certain condition, NLRP3 knock-out induces RA. A dash line indicates knock-out of NLRP3 gene. (B) The SNPs of NLRP1 and the gene expression of NLRP3 are increased in SLE compared to healthy normal control. The activation of NLRP3 inflammasome by the assembly with ASC and pro-caspase-1 is induced in RA compared to healthy normal control. Intracellular AIM2 level is increased in SLE compared to healthy normal control. In contrast, in a certain condition, intracellular levels of NLRP1, NLRP3, and AIM2 are decreased in SLE compared to healthy normal control. Dash lines indicate the decrease in the intracellular levels of NLRP1, NLRP3, and AIM2. (C) The SNPs of CARD, a critical domain of NLRs are increased in AS compared to healthy normal control. Intracellular levels of IL-1 and caspase-1that are down-stream effector molecules of inflammasomes are increased in AS compared to healthy normal control. (D) The gene expression of NLRP3 and intracellular NLRP3 level are increased in SS compared to healthy normal control. The activation of NLRP3 inflammasome by the assembly with ASC and pro-caspase-1 is induced in RA compared to healthy normal control. SNPs, single nucleotide polymorphisms; NRL, nucleotide-binding oligomerization domain-like receptor; RA, rheumatoid arthritis; SLE, systemic lupus erythematosus; AS, ankylosing spondylitis; SS, Sjögren's syndrome.

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