Caspase-1 but Not Caspase-11 Is Required for NLRC4-Mediated Pyroptosis and Restriction of Infection by Flagellated Legionella Species in Mouse Macrophages and In Vivo.

Gram-negative bacteria from the Legionella genus are intracellular pathogens that cause a severe form of pneumonia called Legionnaires' disease. The bacteria replicate intracellularly in macrophages, and the restriction of bacterial replication by these cells is critical for host resistance. The activation of the NAIP5/NLRC4 inflammasome, which is readily triggered in response to bacterial flagellin, is essential for the restriction of bacterial replication in murine macrophages. Once activated, this inflammasome induces pore formation and pyroptosis and facilitates the restriction of bacterial replication in macrophages. Because investigations related to the NLRC4-mediated restriction of Legionella replication were performed using mice double deficient for caspase-1 and caspase-11, we assessed the participation of caspase-1 and caspase-11 in the functions of the NLRC4 inflammasome and the restriction of Legionella replication in macrophages and in vivo. By using several species of Legionella and mice singly deficient for caspase-1 or caspase-11, we demonstrated that caspase-1 but not caspase-11 was required for pore formation, pyroptosis, and restriction of Legionella replication in macrophages and in vivo. By generating F1 mice in a mixed 129 × C57BL/6 background deficient (129 × Casp-11(-/-) ) or sufficient (129 × C57BL/6) for caspase-11 expression, we found that caspase-11 was dispensable for the restriction of Legionella pneumophila replication in macrophages and in vivo. Thus, although caspase-11 participates in flagellin-independent noncanonical activation of the NLRP3 inflammasome, it is dispensable for the activities of the NLRC4 inflammasome. In contrast, functional caspase-1 is necessary and sufficient to trigger flagellin/NLRC4-mediated restriction of Legionella spp. infection in macrophages and in vivo.

Cerqueira DM ，Pereira MS ，Silva AL ，Cunha LD ，Zamboni DS ... -  《-》

Inhibition of caspase-1 or gasdermin-D enable caspase-8 activation in the Naip5/NLRC4/ASC inflammasome.

Mascarenhas DPA ，Cerqueira DM ，Pereira MSF ，Castanheira FVS ，Fernandes TD ，Manin GZ ，Cunha LD ，Zamboni DS ... -  《-》

Caspase-7 activation by the Nlrc4/Ipaf inflammasome restricts Legionella pneumophila infection.

Akhter A ，Gavrilin MA ，Frantz L ，Washington S ，Ditty C ，Limoli D ，Day C ，Sarkar A ，Newland C ，Butchar J ，Marsh CB ，Wewers MD ，Tridandapani S ，Kanneganti TD ，Amer AO ... -  《-》

Activation of NLRC4 by flagellated bacteria triggers caspase-1-dependent and -independent responses to restrict Legionella pneumophila replication in macrophages and in vivo.

Pereira MS ，Morgantetti GF ，Massis LM ，Horta CV ，Hori JI ，Zamboni DS ... -  《-》

Gasdermin-D and Caspase-7 are the key Caspase-1/8 substrates downstream of the NAIP5/NLRC4 inflammasome required for restriction of Legionella pneumophila.

Gonçalves AV ，Margolis SR ，Quirino GFS ，Mascarenhas DPA ，Rauch I ，Nichols RD ，Ansaldo E ，Fontana MF ，Vance RE ，Zamboni DS ... -  《-》