Editors' ChoiceInflammation

Complementing caspase 11

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Science Signaling  01 Nov 2016:
Vol. 9, Issue 452, pp. ec254
DOI: 10.1126/scisignal.aal2951

The cytosolic protease caspase 11 senses and is activated by the microbial product lipopolysaccharide (LPS), which leads to cell death by pyroptosis and the activation of caspase 1, which is required for secretion of the proinflammatory cytokines interleukin-1β (IL-1β) and IL-18. Uncontrolled cell death and inflammatory cytokine production in infected patients result in sepsis, which is often fatal. Napier et al. performed a CRISPR/Cas9-based screen in a mouse macrophage cell line and found that loss of the gene encoding the complement-related peptidase carboxypeptidase B1 (Cpb1) reduced caspase 11–dependent death in cells exposed to cytosolic LPS. Cpb1 processes a cleavage product of the complement factor C3a to generate a ligand for the G protein–coupled receptor C3aR. Knockout of Cpb1 in a mouse macrophage cell line also decreased activation of caspase 11 and reduced expression of the gene encoding caspase 11 in cells exposed to LPS. Incubation of Cbp1-deficient macrophages with conditioned medium from LPS-treated wild-type or C3aR-deficient macrophages (both of which contained functional Cbp1) led to the expression of genes encoding inflammatory cytokines; however, conditioned medium from LPS-treated Cbp1-deficient macrophages had no such effect, suggesting that the Cbp1-C3-C3aR pathway acts in both a cell-autonomous and non–cell-autonomous manner. Macrophages deficient in Cpb1, C3, or C3aR were as protected from death induced by bacterial infection as were macrophages deficient in caspase 11. Compared with wild-type mice, C3aR-deficient mice had decreased serum concentrations of inflammatory cytokines and increased survival in response to injection with LPS. Furthermore, treatment of wild-type mice with a pharmacological inhibitor of C3aR protected them from the effects of LPS. Exposure of human macrophages to cytosolic LPS led to increased expression of the genes encoding caspases 4 and 5, orthologs of mouse caspase 11, which was blocked by the C3aR inhibitor. Last, compared with healthy controls, human sepsis patients showed increased expression of the genes encoding caspase 5 and C3aR. Together, these data suggest that the Cbp1-C3-C3aR axis enhances caspase 11–dependent inflammation and sepsis, providing a potentially useful therapeutic target for treating sepsis.

B. A. Napier, S. W. Brubaker, T. E. Sweeney, P. Monette, G. H. Rothmeier, N. A. Gertsvolf, A. Puschnik, J. E. Carette, P. Khatri, D. M. Monack, Complement pathway amplifies caspase-11–dependent cell death and endotoxin-induced sepsis severity. J. Exp. Med. 213, 2365–2382 (2016). [PubMed]

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