Contribution of Toll-Like Receptors and the NLRP3 Inflammasome in Rheumatoid Arthritis Pathophysiology

Figures & data

Figure 1 Pathological changes in a rheumatoid arthritis joint. In established RA, the inflamed synovial membrane forms a pannus, due to infiltration of peripheral blood cells and proliferation of fibroblast-like synoviocytes. These cells are highly activated releasing pro-inflammatory mediators and autoantibodies within the joint sustaining the inflammatory process. This is accompanied by cartilage damage and osteoclast-mediated bone erosion leading to invasion of the pannus tissue and irreversible deformation of the joint.

Figure 2 Two signal model for classical NLRP3 inflammasome activation by TLR4. During the priming stage, activation of TLR4 by MAMPs or DAMPs upregulates NLRP3 and pro-IL-1β expression through NF-κB activation. This is closely followed by activation and assembly of the NLRP3 inflammasome, which can be induced by various stimuli including K⁺ efflux, Ca²⁺ signaling, mitochondrial dysfunction, and lysosomal rupture. Upon activation, caspase-1 cleaves pro-IL-1β and GSDMD resulting in pyroptosis and IL-1β release. Created with BioRender.com.

Abbreviations: TLR, toll-like receptor; MAMPs, microbe associated molecular patterns; DAMPs, damage-associated molecular patterns; MAL, MyD88 adaptor-like; MyD88, myeloid differentiation primary response 88; IRAK, IL-1R–associated kinase; TRIF, TIR-domain-containing adaptor protein-inducing IFN-β; TRAM, TRIF-related adaptor molecule; TRAF, TNF receptor-associated factor; TAK, TGF-β-activated kinase; TAB, TAK1 binding protein; NEMO, NF-κB essential modulator; IKK, IκB kinase; NF-κB, nuclear factor-κB; NLRP3, nucleotide-binding domain and leucine-rich repeat pyrin containing protein-3; IL, interleukin; ASC, apoptosis-associated speck/like protein containing a CARD; GSDMD, gasderminD; ROS, reactive oxygen species.

Table 1 Endogenous Toll-Like Receptor Ligands Associated with Rheumatoid Arthritis

TLRs	Endogenous Ligands
TLR2	High-Mobility-Group-Protein B1^Citation37
	Heat shock protein 96^Citation39
	Serum amyloidA^Citation127
	SNAP-associated protein^Citation128
	Heat shock protein 60^Citation34
TLR3	RNA released by necrotic synovial fluid cells^Citation54
TLR4	High-Mobility-Group-Protein B1^Citation37
	Citrullinated fibrinogen-containing immune complexes^Citation69
	Tenascin-C^Citation129
	S100 Calcium Binding Protein A8^Citation130
	Soluble biglycan^Citation131
	Heat shock protein B8^Citation132
	Heat shock protein 96^Citation39
	Heat shock protein 60^Citation34
	Alpha-enolase^Citation133
TLR5	High-Mobility-Group-Protein B1^Citation76
TLR7	Single-stranded RNA^Citation81
	miR-let-7b^Citation88
	Small extracellular vesicles -derived-miR-574-5p^Citation87
TLR8	Small extracellular vesicles -derived-miR-574-5p^Citation87
TLR9	DNA fragments^Citation94,Citation134
TLR10

Abbreviation: TLR, toll-like receptor.

Table 2 Summary of Some of the Main Associations of TLRs with RA Pathogenesis in Human and Animal Disease Models

	Rheumatoid Arthritis	Experimental Animal Models
Altered TLR expression	↑TLR1,^Citation35,Citation36 ↑TLR2,^Citation33^–^Citation35 ↑TLR3,^Citation51,Citation52 ↑TLR4,^Citation35,Citation51,Citation63^–^Citation66 ↑TLR5,^Citation77 ↑TLR8,^Citation35,Citation36,Citation81 ↑TLR9,^Citation33,Citation56,Citation95 ↑TLR10 in B cells^Citation104 and NK cells^Citation103 and ↓TLR10 in PBMCs from active RA vs inactive.^Citation101	↑TLR2^Citation46^–^Citation48 (pre-onset of disease in CIA^Citation35) ↑TLR3 (CIA model, Rat PIA model)^Citation59,Citation61
Association with disease activity	DAS28 correlates with TLR1/2 induced IL-6 from RA monocytes^Citation40 and expression of monocyte TLR5^Citation77 and TLR7.^Citation81 Synovial TLR4 expression correlates with synovitis.^Citation36 Patients expressing the less inflammatory TLR8 M1V variant exhibit reduced disease severity.^Citation82 TLR10 missense mutation associated with increased disease severity.^Citation102 ↑TLR10 expression in B cells^Citation104 and ↓TLR10 in PBMCs^Citation101 associated with active disease and increased severity.	Murine CIA model: TLR4 andTLR7 deficient mice and therapeutic inhibition of TLR4 or the endosomal TLRs reduces disease severity.^Citation71,Citation73,Citation85,Citation89,Citation90 HTLR8tg mice are more susceptible to CIA.^Citation93 TLR9 activation by apoptotic cells is protective.^Citation96 Rat CIA model: Intraarticular knockdown of TLR7 reduced disease.^Citation91 Rat PIA model: MiRNA suppression of TLR3 reduces disease.^Citation60 Prophylactic TLR9 inhibition reduces disease onset.^Citation99 IL-1Ra-/- spontaneous arthritis model: TLR2-/- more severe disease.^Citation49 Inhibition of TLR4 suppresses disease.^Citation73 SCW model: TLR2-/-^Citation50 and TLR9-/-^Citation99 show reduced severity. K/BxN serum transfer model: TLR9-/-^Citation99 no effect, TLR4-/- mice are protected.^Citation72 Intraarticular injection of bacterial DNA induces arthritis in C57/BL6 mice.^Citation97 AIA rat model: TLR4 antagonist reduces joint inflammation and bone damage.^Citation74
Pro-inflammatory cytokine production	Activation of TLR1/2 and TLR2/6.^Citation33,Citation40,Citation41 TLR4 activated RA SF macrophages^Citation65 and TLR5 activated monocytes induce elevated cytokines.^Citation40 Inhibition of TLR2^Citation45 and TLR8^Citation83^–^Citation85 reduces spontaneous cytokine release from RA synovial tissue.	TLR8 expression correlates with pro-inflammatory joint cytokines in hTLR8tg CIA.^Citation93 Inhibition of TLR4 suppresses disease and reduces cytokine release from FLS in the AIA rat model.^Citation74
Osteoclasto-genesis	TLR2,^Citation42 TLR3,^Citation58 TLR5,^Citation78 TLR7 and TLR8^Citation87	TLR4 (CIA model),^Citation70 TLR5 (CIA model)^Citation78 and TLR9 (rat PIA model)^Citation99
Cell invasion/ migration	TLR2^Citation44,Citation45 TLR5^Citation78

Abbreviations: AIA, adjuvant induced-arthritis; CIA, collagen-induced arthritis; DAS28, disease activity score 28; FLS, fibroblast-like synoviocytes; hTLR8tg, human TLR8 transgenic; IL, interleukin; IL-1Ra, IL-1 receptor antagonist; M1V, methionine1valine; miRNA, microRNA; NK cells, natural killer cells; PBMCs, peripheral blood mononuclear cells; PIA, pristane-induced arthritis; RA, rheumatoid arthritis; SCW, streptococcal cell wall; SF, synovial fluid; TLR, toll-like receptor; ↑, upregulated; ↓, downregulated.

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