Regulation, Activation and Function of Caspase-11 during Health and Disease

Abstract

Caspase-11 is a pro-inflammatory enzyme that is stringently regulated during its expression and activation. As caspase-11 is not constitutively expressed in cells, it requires a priming step for its upregulation, which occurs following the stimulation of pathogen and cytokine receptors. Once expressed, caspase-11 activation is triggered by its interaction with lipopolysaccharide (LPS) from Gram-negative bacteria. Being an initiator caspase, activated caspase-11 functions primarily through its cleavage of key substrates. Gasdermin D (GSDMD) is the primary substrate of caspase-11, and the GSDMD cleavage fragment generated is responsible for the inflammatory form of cell death, pyroptosis, via its formation of pores in the plasma membrane. Thus, caspase-11 functions as an intracellular sensor for LPS and an immune effector. This review provides an overview of caspase-11-describing its structure and the transcriptional mechanisms that govern its expression, in addition to its activation, which is reported to be regulated by factors such as guanylate-binding proteins (GBPs), high mobility group box 1 (HMGB1) protein, and oxidized phospholipids. We also discuss the functional outcomes of caspase-11 activation, which include the non-canonical inflammasome, modulation of actin dynamics, and the initiation of blood coagulation, highlighting the importance of inflammatory caspase-11 during infection and disease.

Keywords: Caspase-11; Gasdermin D; Gram-negative bacterial infection; non-canonical inflammasome; pyroptosis; sepsis.

Figure 1

Caspase-11 structural domains. Caspase-11 is comprised of three domains; the N-terminal CARD domain is separated from the large subunit (26 kDa) by a CARD domain linker region (CDL). The large subunit and C-terminal small subunit (10 kDa) are the catalytic domains, separated by the inter-domain linker region (IDL). Caspase-11 auto-proteolysis involves CDL cleavage at D59 and D80 to remove the CARD domain. The large and small catalytic domains are separated by processing of IDL at D285, to generate subunits P10 and P26 or P32. The active cysteine residue C254 is located within the enzymatic active site of the large subunit.

Figure 2

Caspase-11 upregulation occurs as a result of PAMP and/or cytokine signaling and can be amplified by complement signaling. TLR signaling—Exogenous PAMPs, such as LPS, that signal through TLRs result in MYD88-dependant activation of NF-κB. Endocytosed LPS-TLR4 signals through the TRIF adaptor protein, resulting in the activation of IRF3 and IRF7 and activation of type I IFNs, which are responsible for caspase-11 upregulation downstream of LPS. IL-1β signaling—IL-1β signals through the IL-1 receptor complex, which results in MYD88-dependant NF-κB activation and Type I IFN signaling. IL-1β-mediated upregulation of caspase-11 is dependent on type I IFN-signaling. Type I IFN signaling—IFNα/β, which is also generated following LPS and IL-1β stimulation, signals through IFNAR. This results in phosphorylation of STAT1/STAT2 and formation of the ISGF3 transcriptional complex, which significantly upregulates caspase-11. Caspase-11 upregulation via Type I IFNs, LPS, or IL-1β is significantly impaired in Ifnar^−/− BMDM, highlighting the importance of IFNAR signaling for caspase-11 expression. Type II IFN signaling—IFNγ signals through the IFNGR, resulting in the formation of a phospho-STAT1 dimer, which is capable of directly upregulating genes, such as caspase-11, which have IFN-stimulatory-gene (ISG) promoter sequences. Complement pathway—the complement protein cleavage product, C3a, is modified to C3a-desArg by the carboxypeptdidase Cpb1, which is associated with the C3a receptor (C3aR). The modified cleavage product then signals through C3aR, resulting in downstream activation of the MAPK pathway. This pathway acts to amplify p38 activation downstream of TLR4 and IFNAR signaling, boosting caspase-11 expression.

Figure 3

Effector functions of caspase-11. Cytosolic LPS (via GBPs) binds and activates caspase-11, which leads to: Non-canonical inflammasome activation and pyroptosis—direct cleavage of GSDMD by caspase-11, generating the pore-forming P30 N-terminal fragment (GSDMD-NT) and membrane permeable pores, which passively release alarmins, IL-1α, and HMGB1. Caspase-11 activation also triggers NLRP3 inflammasome activation, leading to maturation and release of IL-1β and IL-18. Caspase-11 also cleaves Pannexin-1, mediating ATP release and K⁺ efflux to trigger activation of the NLRP3 inflammasome. Actin polymerization—Activated caspase-11 directly interacts with Aip-1 leading to cofilin dephosphorylation and activation of cellular migration. During Gram-negative bacterial infection, cofilin drives actin remodeling, leading to phagolysosomal fusion and bacterial clearance. However, during MRSA infection, caspase-11 promotion of actin remodeling drives dissociation of mitochondria from MRSA-containing vacuoles, reducing the contribution of mitochondrial ROS to bacterial clearance, enhancing the persistence of MRSA. Coagulation—Caspase-11 and GSDMD-N pore formation mediates Ca²⁺ influx allowing phosphatidylserine (PS) externalization to the outer plasma membrane. Exposed PS interacts with tissue factor (TF), which associates with complement factors to initiate the coagulation cascade. The GSDMD-mediated Ca²⁺ influx also mediates a membrane repair response via ESCRT components, removing GSDMD pores and repairing membrane integrity.