Caspase-7 Activation by the Nlrc4/Ipaf Inflammasome Restricts Legionella pneumophila Infection

Abstract

Legionella pneumophila (L. pneumophila), the causative agent of a severe form of pneumonia called Legionnaires' disease, replicates in human monocytes and macrophages. Most inbred mouse strains are restrictive to L. pneumophila infection except for the A/J, Nlrc4−/− (Ipaf−/−), and caspase-1−/− derived macrophages. Particularly, caspase-1 activation is detected during L. pneumophila infection of murine macrophages while absent in human cells. Recent in vitro experiments demonstrate that caspase-7 is cleaved by caspase-1. However, the biological role for caspase-7 activation downstream of caspase-1 is not known. Furthermore, whether this reaction is pertinent to the apoptosis or to the inflammation pathway or whether it mediates a yet unidentified effect is unclear. Using the intracellular pathogen L. pneumophila, we show that, upon infection of murine macrophages, caspase-7 was activated downstream of the Nlrc4 inflammasome and required caspase-1 activation. Such activation of caspase-7 was mediated by flagellin and required a functional Naip5. Remarkably, mice lacking caspase-7 and its macrophages allowed substantial L. pneumophila replication. Permissiveness of caspase-7−/− macrophages to the intracellular pathogen was due to defective delivery of the organism to the lysosome and to delayed cell death during early stages of infection. These results reveal a new mechanism for caspase-7 activation downstream of the Nlrc4 inflammasome and present a novel biological role for caspase-7 in host defense against an intracellular bacterium.

CASP4/caspase-11 promotes autophagosome formation in response to bacterial infection

“…Cleaved CASP7, as a result of CASP1 activation, has been described for S . Typhimurium [29], L. pneumophila [30] and B. pseudomallei [39] infection, all of which are pathogens predominantly sensed by the NLRC4 inflammasome [16]. Thus, our results demonstrate that CASP1-dependent CASP7 activation is not restricted to the NLRC4 inflammasome.…”

“…Because CASP7 (caspase 7) is a known substrate of CASP1 [29,30], we further evaluated if CASP4 affected CASP7 activation. Indeed, B. cenocepacia induced cleavage of CASP7 in WT macrophages, which was significantly reduced in casp4 −/- macrophages (Fig.…”

“…For the generation of primary bone marrow-derived macrophages from mice, tibias and femurs were flushed with IMDM medium (Thermo Fisher Scientific, 12,440,053) supplemented with 10% fetal bovine serum (Thermo Fisher Scientific, 16,000,044), 50% L cell-conditioned medium [66,67], 0.6x MEM non-essential amino acids (Thermo Fisher Scientific, 11,140,050) and 0.1% penicillin and streptomycin (Thermo Fisher Scientific, 15,140,122) as previously described [5,16,25,30,41,65]. Cells were cultivated at least 6 days at 37°C in a humidified atmosphere containing 5% CO 2 .…”

Programmed cell death in the plant immune system

“…The caspase-1 digestome includes chaperones, cytoskeletal maintenance components and proteins involved in energy metabolism, 37 as well as caspase-7, 38 which has been shown to be activated downstream of NLRC4 inflammasome during bacterial infection. 39 However, it is still not clear why pyroptotic cells die. Permeabilization of the plasma membrane, which presumably participates in protein secretion at early stages of pyroptosis, can be the cause of later cell death due to ruptures caused by cytoplasmic swelling.…”

Caspases as the Key Effectors of Inflammatory Responses Against Bacterial Infection

“…Mice and macrophages lacking caspase-7 allow substantial L. pneumophila replication. It has been shown that caspase-7 is involved in the maturation of L. pneumophila-containing phagosomes and induces cell death in infected macrophages (Akhter et al 2009). In addition, caspase-7 contributes to the activation of NF-jB through the cleavage of PARP1 in response to LPS stimulation in macrophages (Erener et al 2012); however, it is not clear whether this mechanism is involved in the inflammatory response towards genuine bacterial infection.…”