Expression and function of the NALP3 inflammasome in rheumatoid synovium

Abstract

Summary The NACHT, LRR and PYD domains containing protein (NALP3) inflammasome is a key regulator of interleukin‐1β (IL‐1β) secretion. As there is strong evidence for a pro‐inflammatory role of IL‐1β in rheumatoid arthritis (RA) and in murine models of arthritis, we explored the expression of the different components of the NALP3 inflammasome as well as other nucleotide oligomerization domain (NOD)‐like receptors (NLRs) in synovium obtained from patients with RA. The expression of NLRs was also studied in fibroblast lines derived from joint tissue. By immunohistology, NALP3 and apoptosis‐associated speck‐like protein containing a CARD domain (ASC) were expressed in myeloid and endothelial cells and B cells. T cells expressed ASC but lacked NALP3. In synovial fibroblast lines, NALP3 expression was not detected at the RNA and protein levels and stimulation with known NALP3 agonists failed to induce IL‐1β secretion. Interestingly, we were unable to distinguish RA from osteoarthritis synovial samples on the basis of their basal level of RNA expression of known NLR proteins, though RA samples contained higher levels of caspase‐1 assayed by enzyme‐linked immunsorbent assay. These results indicate that myeloid and endothelial cells are the principal sources of inflammasome‐mediated IL‐1β production in the synovium, and that synovial fibroblasts are unable to activate caspase‐1 because they lack NALP3. The NALP3 inflammasome activity does not account for the difference in level of inflammation between RA and osteoarthritis.

Inflammasome Adaptor Protein Apoptosis-Associated Speck-Like Protein Containing CARD (ASC) Is Critical for the Immune Response and Survival in West Nile Virus Encephalitis

“…ASC has been identified as the regulator of NF-B and MAPK/ERK-2 activity in murine and human monocytes/ macrophages (42,43). The disease progression in the mouse model of autoimmune arthritis is attenuated in mice lacking ASC, but not in caspase 1 Ϫ/Ϫ mice (44,45). Further, Ichinohe et al reported that nasal IgA and systemic IgG responses against influenza virus required ASC, but not NLRP3 (26).…”

NLRP3 inflammasome plays a critical role in the pathogenesis of hydroxyapatite-associated arthropathy

“…Expression of the inflammasome components in OA synovium has been described and active caspase-1 has been detected with markedly increased cellularity in articular cartilage of human OA (36)(37)(38). Here we demonstrated that in comparison with the human monocytic cell line THP1, the expressions of ASC, caspase-1, and especially NLRP3 mRNA were very low in CD33 − nonhematopoietic cells, including primary human chondrocytes and synoviocytes derived from OA patients (Fig.…”

Inflammatory osteolysis: a conspiracy against bone

“…The NLRP3 inflammasome is also activated in RA synovium, consistent with increased IL-1β secretion (110,111). TNF-α stimulates IL-1β expression in vitro, suggesting the latter cytokine may drive pro-IL-1β transcription in RA.…”