Inflammatory arthritis in caspase 1 gene–deficient mice: Contribution of proteinase 3 to caspase 1–independent production of bioactive interleukin‐1β

Abstract

Objective. Caspase 1, a known cysteine protease, is a critical component of the inflammasome. Both caspase 1 and neutrophil serine proteases such as proteinase 3 (PR3) can process pro-interleukin-1␤ (proIL-1␤), a crucial cytokine linked to the pathogenesis of rheumatoid arthritis. This study was undertaken to establish the relative importance of caspase 1 and serine proteases in mouse models of acute and chronic inflammatory arthritis.Methods. Acute and chronic arthritis were induced in caspase 1 ؊/؊ mice, and the lack of caspase 1 was investigated for its effects on joint swelling, cartilage metabolism, and histopathologic features. In addition, caspase 1 activity was inhibited in mice lacking active cysteine proteases, and the effects of dual blockade of caspase 1 and serine proteases on arthritis severity and histopathologic features were evaluated.Results. Conclusion. Caspase 1 deficiency does not affect neutrophil-dominated joint inflammation, whereas in chronic arthritis, the lack of caspase 1 results in reduced joint inflammation and cartilage destruction. These findings suggest that inhibitors of caspase 1 are not able to interfere with the whole spectrum of IL-1␤ production, and therefore such inhibitors may be of therapeutic value only in inflammatory conditions in which limited numbers of neutrophils are present.Cytokines, such as interleukin-1␤ (IL-1␤), that are produced by cells of the innate immune system are induced in response to a variety of pathogen-or damage-associated molecular patterns. Because of its potent inflammatory properties, IL-1␤ can be deleterious if released in high amounts in various sites of the body (1). Both the production and activity of IL-1␤ are tightly regulated at several levels, including during transcription and translation (2), conversions of the inactive

IL-33 is processed into mature bioactive forms by neutrophil elastase and cathepsin G

“…IL-33 has been shown to play important roles in mouse models of rheumatoid arthritis (12,13) and to orchestrate neutrophil migration into the joints (41). Neutrophil serine proteases are critical for IL-1β processing in the acute phase of arthritis, characterized by a strong neutrophilic infiltrate (36,37), and could also mediate IL-33 processing into mature bioactive forms in inflammatory arthritis. Finally, processing of IL-33 by neutrophils proteases may also occur during bacterial, fungal or viral infections.…”

“…Interestingly, caspase-1-independent activation of IL-1β and IL-18 has been reported in several studies (1, 3, 34-37, 42, 43). Neutrophil serine proteases cathepsin G, elastase, and proteinase-3 (PR3) have been shown to cleave the IL-1β precursor a few residues upstream the caspase-1 maturation site and to produce mature bioactive forms of the cytokine (1,3,(34)(35)(36)(37). Extracellular processing of IL-33 into mature bioactive forms by neutrophil serine proteases is, thus, a mechanism shared with other IL-1 family members.…”

Critical role for inflammasome-independent IL-1β production in osteomyelitis

“…Although caspase-1-mediated secretion of IL-1β is the most well characterized mechanism for IL-1β activation, other inflammasomeindependent sources of IL-1β have also been reported to contribute to autoinflammatory disease pathogenesis (10,12). Caspase-1-independent IL-1β has been described to play crucial roles in osteoarthritis (29), particulate-induced lung inflammation (30), host defense against certain pathogens (31,32), and other inflammatory diseases (33). Our findings suggest that PSTPIP2-targeted therapies may prove helpful in the treatment of such diseases.…”

NADPH oxidase derived reactive oxygen species are involved in human neutrophil IL‐1β secretion but not in inflammasome activation

“…Previous studies have documented that human neutrophils express both NLRP3 and caspase-1 [15][16][17][18]. However, as neutrophil proteases were also implicated both in extracellular and intracellular pro-IL-1β processing [5,[19][20][21][22], the idea that prevails is that these cells process pro-IL-1β through a protease-dependent and caspase-1-independent mechanism [4].…”

“…Previous studies have documented that human neutrophils express both NLRP3 and caspase-1 [15][16][17][18]. However, as neutrophil proteases were also implicated both in extracellular and intracellular pro-IL-1β processing [5,[19][20][21][22], the idea that prevails is that these cells process pro-IL-1β through a protease-dependent and caspase-1-independent mechanism [4].In the current study, we demonstrate that both serine-proteasedependent and caspase-1-dependent mechanisms contribute to IL-1β processing and secretion in human neutrophils. Our results identify a never before described role of ROS in the release of mature IL-1β, and show that ROS are not required for inflammasome activation and IL-1β processing in neutrophils.…”