Inflammasomes and their roles in arthritic disease pathogenesis

Abstract

The inflammasome is a molecular platform that is created in the cytosolic compartment to mediate the host immunological response to cellular injury and infection. Caspase-1 may be activated by the inflammasome, which leads to the generation of the inflammatory cytokines interleukin-1β (IL-1β) and IL-18 and the beginning of pyroptosis, which is a type of proinflammatory cell death. Scientists have identified a number of different inflammasomes in the last 2 decades. The NLRP3 inflammasome has been studied the most, and its activity may be triggered by a broad range of different inducers. However, activation of the NLRP3 inflammasome in a manner that is not properly controlled is also a factor in the etiology of many human illnesses. Accumulating evidence indicates that the NLRP3 inflammasome plays a significant role in the innate and adaptive immune systems and the development of various arthritic illnesses, such as rheumatoid arthritis, ankylosing spondylitis, and gout. The present review provides a concise summary of the biological properties of the NLRP3 inflammasome and presents the fundamental processes behind its activation and control. We discuss the role of the inflammasome in the pathogenesis of arthritic diseases, such as rheumatoid arthritis, ankylosing spondylitis, and gout, and the potential of newly developed therapies that specifically target the inflammasome or its products for the treatment of inflammatory diseases, with a particular emphasis on treatment and clinical application.

Keywords: immunity; inflammation; pattern recognition receptors; pharmacological inhibitors; therapeutic targets.

FIGURE 1

The signaling pathways for inflammasome activation in rheumatoid arthritis. Overexpression of TNF-α in the synovial macrophages of rheumatoid arthritis joints leads to activation of the classical NF-κB pathway, which leads to activation of the transcription factor RelA. RelA constructively regulates the expression of NLRP3. In conclusion, a higher level of NLRP3 expression results in more robust activation of the NLRP3 inflammasome.

FIGURE 2

DAMPs produced upon synovial tissue damage regulate immune responses. DAMP molecules activate immune cells after cell injury, infection, or inflammation. Innate immune system may enhance and alleviate inflammation by eliminating or modulating adaptive immune responses, e.g., through regulatory T cells. Positive feedback loops involving DAMPs increase leukocyte recruitment and cause persistent rheumatoid arthritis.

FIGURE 3

Activation of the inflammasome by monosodium uric acid crystals in the induction of gouty arthritis symptoms. TLR receptors are activated, and inflammasome formation is mediated by monosodium uric acid crystals. Once the inflammasome is activated, caspase-1 is also activated, which allows for the cleavage of GSDMD, pro-IL-1β, and pro-IL-18. Active IL-1 and IL-18 may be exported to the extracellular space via a transmembrane channel formed by the N-terminal GSDMD.

FIGURE 4

Targeting inflammasomes by inhibitors and the molecular targets of some anti-inflammatory drugs. The red box shows a list of inhibitors that stop the inflammasome function, but the molecular targets are unknown.