Inflammasomes-New Contributors to Blood Diseases

Abstract

Inflammasomes are intracellular multimeric complexes that cleave the precursors of the IL-1 family of cytokines and various proteins, found predominantly in cells of hematopoietic origin. They consist of pattern-recognition receptors, adaptor domains, and the enzymatic caspase-1 domain. Inflammasomes become activated upon stimulation by various exogenous and endogenous agents, subsequently promoting and enhancing inflammatory responses. To date, their function has been associated with numerous pathologies. Most recently, many studies have focused on inflammasomes' contribution to hematological diseases. Due to aberrant expression levels, NLRP3, NLRP1, and NLRC4 inflammasomes were indicated as predominantly involved. The NLRP3 inflammasome correlated with the pathogenesis of non-Hodgkin lymphomas, multiple myeloma, acute myeloid leukemia, lymphoid leukemias, myelodysplastic neoplasms, graft-versus-host-disease, and sickle cell anemia. The NLRP1 inflammasome was associated with myeloma and chronic myeloid leukemia, whereas NLRC4 was associated with hemophagocytic lymphohistiocytosis. Moreover, specific gene variants of the inflammasomes were linked to disease susceptibility. Despite the incomplete understanding of these correlations and the lack of definite conclusions regarding the therapeutic utility of inflammasome inhibitors, the available results provide a valuable basis for clinical applications and precede upcoming breakthroughs in the field of innovative treatments. This review summarizes the latest knowledge on inflammasomes in hematological diseases, indicates the potential limitations of the current research approaches, and presents future perspectives.

Keywords: NLR-family-CARD-domain-containing-protein-4 (NLRC4); NLR-family-pyrin-domain-containing-3 (NLRP3); NLRP1; hematology; inflammasome; leukemia; lymphoma; myeloma.

Figure 1

The components of the inflammasome complex—A general scheme. PRR—A component that detects inflammasome activation signals. ASC—An adaptor protein enabling association of PRR with pro-caspase-1. Pro-caspase-1—An effector component of the inflammasome complex. PYD domains—Domains enabling the association of PRR with ASC. CARD domains—Domains enabling the association of pro-caspase-1 with the PRR–ASC complex. Abbreviations: PRR—Pattern-recognition receptor; ASC—Apoptosis-associated speck-like protein containing a caspase-recruitment domain; PYD—Pyrin domain; CARD—Caspase activation and recruitment domain. Created with BioRender.com (accessed on 10 May 2022).

Figure 2

Simplified priming and activation mechanisms of the NLRP3 inflammasome. Signal 1—Priming: detection of specific DAMPs or PAMPs enables transcription and translation of inactive inflammasome components and immature IL-1 family cytokines. Signal 2—Activation: the NLR domain recognizes specific activators that elicit the association of inflammasome components and subsequent assembly of the whole inflammasome complex. Then, the inflammasome cleaves its substrates, predominantly IL-1β and IL-18 cytokines, leading to the inflammatory response. Cleavage of gasdermin D leads to the creation of membrane pores and a specific type of cell death, pyroptosis. Created with BioRender.com (accessed on 11 July 2022).

Figure 3

The summary of the inflammasome-modulating approaches. Interleukin blocking agents: antibodies neutralizing cytokines of IL-1 family and their receptors. Small-molecule inhibitors: molecules that directly inhibit the inflammasome components (e.g., MCC950). Other selective inhibitors: molecules selectively inhibiting gasdermin, caspase-1 or proteasome. Dietary modulation: modulating intestinal inflammasome response by change of diet composition. Created with BioRender.com (accessed on 10 July 2022).

Figure 4

The inflammasomes and their involvement in hematological diseases. The NLRP3 inflammasome contributes to the pathogenesis of numerous hematological diseases: several lymphomas, multiple myeloma, acute myeloid leukemia (AML), acute lymphoblastic leukemia (ALL), chronic lymphocytic leukemia (CLL), myelodysplastic neoplasms (MDS), graft versus host disease (GvHD) and sickle cell anemia. The NLRP1 inflammasome contributes to the pathogenesis of multiple myeloma and chronic myeloid leukemia (CML). The NLRC4 inflammasome contributes to the pathogenesis of secondary hemophagocytic lymphohistiocytosis (secondary HLH). Created with BioRender.com (accessed on 10 May 2022).