Abstract
Caspase-1, also known as interleukin-1β (IL-1β)-converting enzyme (ICE), regulates antimicrobial host defense, tissue repair, tumorigenesis, metabolism and membrane biogenesis. On activation within an inflammasome complex, caspase-1 induces pyroptosis and converts pro-IL-1β and pro-IL-18 into their biologically active forms. “ICE−/−” or “Casp1−/−” mice generated using 129 embryonic stem cells carry a 129-associated inactivating passenger mutation on the caspase-11 locus, essentially making them deficient in both caspase-1 and caspase-11. The overlapping and unique functions of caspase-1 and caspase-11 are difficult to unravel without additional genetic tools. Here, we generated caspase-1–deficient mouse (Casp1Null) on the C57BL/6 J background that expressed caspase-11. Casp1Null cells did not release IL-1β and IL-18 in response to NLRC4 activators Salmonella Typhimurium and flagellin, canonical or non-canonical NLRP3 activators LPS and ATP, Escherichia coli, Citrobacter rodentium and transfection of LPS, AIM2 activators Francisella novicida, mouse cytomegalovirus and DNA, and the infectious agents Listeria monocytogenes and Aspergillus fumigatus. We further demonstrated that caspase-1 and caspase-11 differentially contributed to the host defense against A. fumigatus infection and to endotoxemia.
Highlights
Inflammatory caspases, include caspase-1, caspase-4, caspase-5 and caspase-11, contribute to a variety of biological functions[1,2]
We found inducible expression of caspase-11 in WT and Casp1Null Bone marrow-derived macrophages (BMDMs) stimulated with IFN-β, IFN-γor LPS, whereas Casp11−/− BMDMs, as expected, did not (Fig. 1)
We found that A. fumigatus failed to induce the release of IL-1βand IL-18 in Casp1Null and Casp1−/−Casp11−/− bone marrow-derived dendritic cells (BMDCs), whereas maturation of caspase-1 and the release of IL-1βand IL-18 in WT and Casp11−/− BMDCs were observed (Fig. 4A and B)
Summary
Inflammatory caspases, include caspase-1 (human and mouse), caspase-4 (human), caspase-5 (human) and caspase-11 (mouse), contribute to a variety of biological functions[1,2]. Bone marrow-derived macrophages (BMDMs) or dendritic cells (BMDCs) from Casp1Null mice expressed caspase-11 proteins and did not secrete IL-1βand IL-18 or undergo pyroptosis in response to canonical NLRP3, NLRC4 or AIM2 inflammasome activators. Casp1Null BMDMs failed to secrete IL-1βand IL-18, but underwent caspase-11–dependent pyroptosis, in response to non-canonical activation of the inflammasome.
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