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Caspase-11 controls interleukin-1β release through degradation of TRPC1.

ABSTRACT: Caspase-11 is a highly inducible caspase that controls both inflammatory responses and cell death. Caspase-11 controls interleukin 1β (IL-1β) secretion by potentiating caspase-1 activation and induces caspase-1-independent pyroptosis downstream of noncanonical NLRP3 inflammasome activators such as lipopolysaccharide (LPS) and Gram-negative bacteria. However, we still know very little about the downstream mechanism of caspase-11 in regulating inflammation because the known substrates of caspase-11 are only other caspases. Here, we identify the cationic channel subunit transient receptor potential channel 1 (TRPC1) as a substrate of caspase-11. TRPC1 deficiency increases the secretion of IL-1β without modulating caspase-1 cleavage or cell death in cultured macrophages. Consistently, trpc1(-/-) mice show higher IL-1β secretion in the sepsis model of intraperitoneal LPS injection. Altogether, our data suggest that caspase-11 modulates the cationic channel composition of the cell and thus regulates the unconventional secretion pathway in a manner independent of caspase-1.

SUBMITTER: Py BF

PROVIDER: S-EPMC4239700 | biostudies-literature | 2014 Mar

REPOSITORIES: biostudies-literature

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Caspase-11 controls interleukin-1β release through degradation of TRPC1.

Py Bénédicte F BF Jin Mingzhi M Desai Bimal N BN Penumaka Anirudh A Zhu Hong H Kober Maike M Dietrich Alexander A Lipinski Marta M MM Henry Thomas T Clapham David E DE Yuan Junying J

Cell reports 20140313 6

Caspase-11 is a highly inducible caspase that controls both inflammatory responses and cell death. Caspase-11 controls interleukin 1β (IL-1β) secretion by potentiating caspase-1 activation and induces caspase-1-independent pyroptosis downstream of noncanonical NLRP3 inflammasome activators such as lipopolysaccharide (LPS) and Gram-negative bacteria. However, we still know very little about the downstream mechanism of caspase-11 in regulating inflammation because the known substrates of caspase-1 ...[more]

PMID: 24630989

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Project description:Ions released from metal implants have been associated with adverse tissue reactions and are therefore a major concern. Studies with macrophages have shown that cobalt, chromium, and nickel ions can activate the NLRP3 inflammasome, a multiprotein complex responsible for the activation of caspase-1 (a proteolytic enzyme converting pro-interleukin [IL]-1β to mature IL-1β). However, the mechanism(s) of inflammasome activation by metal ions remain largely unknown. The objectives of the present study were to determine if, in macrophages: 1. caspase-1 activation and IL-1β release induced by metal ions are oxidative stress-dependent; and 2. IL-1β release induced by metal ions is NF-κB signaling pathway-dependent. Lipopolysaccharide (LPS)-primed murine bone marrow-derived macrophages (BMDM) were exposed to Co2+ (6-48 ppm), Cr3+ (100-500 ppm), or Ni2+ (12-96 ppm), in the presence or absence of a caspase-1 inhibitor (Z-WEHD-FMK), an antioxidant (L-ascorbic acid [L-AA]), or an NF-κB inhibitor (JSH-23). Culture supernatants were analyzed for caspase-1 by western blotting and/or IL-1β release by ELISA. Immunoblotting revealed the presence of caspase-1 (p20 subunit) in supernatants of BMDM incubated with Cr3+, but not with Ni2+ or Co2+. When L-AA (2 mM) was present with Cr3+, the caspase-1 p20 subunit was undetectable and IL-1β release decreased down to the level of the negative control, thereby demonstrating that caspase-1 activation and IL-1β release induced by Cr3+ was oxidative stress-dependent. ELISA demonstrated that Cr3+ induced the highest release of IL-1β, while Co2+ had no or limited effects. In the presence of Ni2+, the addition of L-AA (2 mM) also decreased IL-1β release, below the level of the negative control, suggesting that IL-1β release induced by Ni2+ was also oxidative stress-dependent. Finally, when present during both priming with LPS and activation with Cr3+, JSH-23 blocked IL-1β release, demonstrating NF-κB involvement. Overall, this study showed that while both Cr3+ and Ni2+ may be inducing inflammasome activation, Cr3+ is likely a more potent activator, acting through oxidative stress and the NF-κB signaling pathway.

Project description:BACKGROUND:Acute-phase response is a systemic reaction to environmental/inflammatory insults and involves production of acute-phase proteins, including serum amyloid A (SAA). Interleukin-1β (IL-1β), a master regulator of neuroinflammation produced by activated inflammatory cells of the myeloid lineage, in particular microglia, plays a key role in the pathogenesis of acute and chronic diseases of the peripheral nervous system and CNS. IL-1β release is promoted by ATP acting at the purinergic P2X7 receptor (P2X7R) in cells primed with toll-like receptor (TLR) ligands. METHODS:Purified (> 99%) microglia cultured from neonatal rat cortex and cerebellum were first primed with the putative TLR4/TLR2 agonist SAA (recombinant human Apo-SAA) or the established TLR4 agonist lipopolysaccharide (LPS) followed by addition of ATP. Expression of genes for the NLRP3 inflammasome, IL-1β, tumor necrosis factor-α (TNF-α), and SAA1 was measured by quantitative real-time polymerase chain reaction (q-PCR). Intracellular and extracellular amounts of IL-1β were determined by ELISA. RESULTS:Apo-SAA stimulated, in a time-dependent manner, the expression of NLRP3, IL-1β, and TNF-α in cortical microglia, and produced a concentration-dependent increase in the intracellular content of IL-1β in these cells. A 2-h 'priming' of the microglia with Apo-SAA followed by addition of ATP for 1 h, resulting in a robust release of IL-1β into the culture medium, with a concomitant reduction in its intracellular content. The selective P2X7R antagonist A740003 blocked ATP-dependent release of IL-1β. Microglia prepared from rat cerebellum displayed similar behaviors. As with LPS, Apo-SAA upregulated SAA1 and TLR2 mRNA, and downregulated that of TLR4. LPS was less efficacious than Apo-SAA, perhaps reflecting an action of the latter at TLR4 and TLR2. The TLR4 antagonist CLI-095 fully blocked the action of LPS, but only partially that of Apo-SAA. Although the TLR2 antagonist CU-CPT22 was inactive against Apo-SAA, it also failed to block the TLR2 agonist Pam3CSK4. CONCLUSIONS:Microglia are central to the inflammatory process and a major source of IL-1β when activated. P2X7R-triggered IL-1β maturation and export is thus likely to represent an important contributor to this cytokine pool. Given that SAA is detected in Alzheimer disease and multiple sclerosis brain, together with IL-1β-immunopositive microglia, these findings propose a link between P2X7R, SAA, and IL-1β in CNS pathophysiology.

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Caspase-11 controls interleukin-1β release through degradation of TRPC1.

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Caspase-11 controls interleukin-1β release through degradation of TRPC1.

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