Table 1.
Summary of studies targeting endoplasmic reticulum stress in rheumatoid arthritis and systemic lupus erythematosus.
| Ref. | System | Treatment | Outcome |
|---|---|---|---|
| [40] | Mouse model of SLE | 4-PBA | ↑ renal expression of BiP •mitigated the development and progression of renal injury |
| [77] | Human mesangial cells exposed to anti-dsDNA antibodies isolated from patients with LN | 4-PBA | ↓ expression of IL-1β, TNF-α and MCP-1 |
| [78] | Bone marrow mesenchymal stem cells of SLE patients | 4-PBA | ↓ apoptosis ↓ protein expression levels of CHOP and JNK1/2 |
| [91] | Human (THP-1) and mouse (RAW 264.7) macrophages activated with epitope encoded by SLE-risk allele DRB1*03:01 in presence of IFNγ | 4-PBA | ↓ activation of proteasomal degradation and UPR pathways •restored intracellular ATP levels •restored mitochondrial membrane potential ↓ mitochondrial ROS ↓ cell death |
| [49] | RA mouse model | 4μ8C | ↓ joint inflammation |
| [62] | Neutrophils from SLE patients | 4μ8C | ↓ mitochondrial ROS generation ↓ immune complex mediated NETosis |
| [53] | Primary cultured human RASFs; adjuvant-induced arthritis (AIA) rat model | STF-083010 | ↓ cell viability of primary cultured human RASFs ↓ synovial activity in AIA mouse model |
| [60] | Mouse model of SLE | STF-083010 | Results for pristane+STF083010 group in comparison to the pristane group: •attenuated XBP1s expression in spleen and splenomegaly • mRNA expression of Xbp1s decreased • no effect on of Xbp1t in blood samples • Less XBP1s-positive and CD19-positive B cells • suppressed B cell activation, plasma cell generation, Ig secretion, generation of B cell activating factors, and levels of TNF-α • no significant changes in serum levels of IL-6 • suppressed dsDNA and anti-Smith antibody generation • no differences observed for ANAs • attenuated Ig deposition in the kidney and renal damage • no differential XBP1s expression was found in the kidneys |
| [61] | Mouse model of SLE | BI09 | • mitigated progression of nephropathy • ↓ lymphocyte infiltration in lungs and liver, levels of autoreactive antibody, plasma cell differentiation and B cell lipid volumes • no effect observed for skin inflammation • levels of autoimmune antibodies were restored after interruption of treatment |
| [75] | RA mouse model | Salubrinal | • ↓ clinical score for arthritis, synovium inflammation, joint damage, degree of bone destruction, and number of osteoclasts in the knee joints • inhibited osteoclast formation and suppresses RANKL-induced NF-kB signaling via P65 degradation |
| [100] | RA mouse model (CIA) | BiP | ↓ development of arthritis |
| [106] | DBA/1, HLA-DR1+/+, or interleukin-4 (IL-4)-knockout mice at the onset of arthritis | BiP (SQ or IV) | •suppressed established CIA in HLA-DR1+/+ and DBA/1 mice ↓ serum levels of anti-collagen IgG antibodies ↑ Th2 cytokines (IL-4) in T cells ↑ production of CII-specific IL-5, IL-10, and IFNγ at the termination of the study •development of severe CIA was prevented by the intravenous transfer of BiP-specific cells at the time of CIA induction in HLA-DR1+/+ mice •BiP failed to ameliorate the development of CIA in IL-4-/-, HLA-DR1+/+ mice |
| [107] | SCID mice with RASM engraftment | BiP (IV) | ↓ cellular infiltrate in RASM transplants ↓ circulating IL-6 ↓ tissue inflammation in the RASM explants •downregulation of all quantifiable features of inflammation, HLA-DR, CD86, IL-6 and TNF-α in RASM transplants |
| [108] | PBMCs from RA patients | BiP | •secretion of an anti-inflammatory profile of cytokines •early stimulation of production of TNF-α •induction of IL-10 •incubation of monocytes in the presence of BiP induced long lasting down-regulation of CD86 and HLA–DR expression |
| [110] | RA mouse model (CIA) | BiP456–475 (PO) | •improvements in course of joint inflammation and histologic scores ↓ CD4+ T cell proliferation ↑ CD4+CD25+FoxP3+ regulatory T cells ↑CD4+FoxP3+ T cells ↑ secretion of IL-10 from T cells |
↑, increased; ↓, reduced; 4-PBA, 4-phenylbutyric acid; 4μ8C, 8-formyl-7-hydroxy-4-methylcoumarin; AIA, adjuvant-induced arthritis; ANA, antinuclear antibodies; BiP, binding immunoglobulin protein; CHOP, CCAAT-enhancer-binding protein homologous protein; CIA, collagen-induced arthritis; IL, interleukin; IV, intravenous; LN, lupus nephritis; MCP-1, monocyte chemoattractant protein-1; PBMC, peripheral blood mononuclear cells; PO, orally; RA, rheumatoid arthritis; RASFs, RA synovial fibroblasts; RASM, Rheumatoid arthritis synovial membrane; ROS, reactive oxygen species; SCID, Severe combined immunodeficient mice; SLE, systemic lupus erythematosus; SQ, subcutaneous; TNF-α, tumor necrosis factor alpha.