Differential roles of caspase-1 and caspase-11 in infection and inflammation

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.

The NLRP6 Inflammasome Recognizes Lipoteichoic Acid and Regulates Gram-Positive Pathogen Infection

“…Nlrp3 −/− , Pycard −/− , Casp11 −/− , Casp1 −/− Casp11 −/− (He et al, 2016), Nlrp6 −/− (Chen et al, 2011), Il18 −/− (Seregin et al, 2017), Aim2 −/− , Il1b −/− (Seo et al, 2015), Casp1 −/− (Man et al, 2017), and Gsdmd −/− mice (Rauch et al, 2017) on C57BL/6 background have been reported. C57BL/6 WT and Ifnar1 −/− (Muller et al, 1994) mice were purchased from Jackson Laboratories.…”

Molecular mechanisms of inflammasome signaling

“…160 LPS and oxAPC elicit caspase-11-induced inflammasome speck formation and IL-1 release, but not pyroptosis, in DCs. 160 In addition, caspase-11 contributes to host resistance to the fungal pathogen Aspergillus fumigatus in vivo, 161 revealing a biologic role for caspase-11 in host defense against pathogens other than Gram-negative bacteria. Overall, substantial advances have been made in our understanding of the noncanonical NLRP3 inflammasome.…”

Checks and Balances between Autophagy and Inflammasomes during Infection

“…In mice, this activation is necessary for early control of L. monocytogenes via production of IL-18 and interferon (IFN)γ. However, caspase-1 appears dispensable for acquisition of sterilizing adaptive immunity and no role for caspase-11 was identified in C57BL/6 mice [47–49]. Using cell culture models, several studies showed that L. monocytogenes activates NLRP3 and AIM2 inflammasomes.…”

“…Thus, physiological (nutrient starvation), pharmacological (rapamycin, sodium valproate, vitamin D), or immunological agonists of autophagy (TNF, IFN-α) stimulate mycobacterial phagosome maturation, allowing the host cell to control M.tb infection [163]. Specifically, IFN-γ acts on promoting autophagy via the induction of TNF and the immunity-related GTPase protein IRGM1 [49–51,167,168]. The role of IRGM1 in induction of autophagy has been well characterized in several human polymorphism studies, as well as the potential role of other closely related to autophagy genes such as P 2 X 7 , VDR, NOD2 , and TLR8 (summarized in Ref.…”