Hierarchical cell-type-specific functions of caspase-11 in LPS shock and antibacterial host defense

Abstract

SUMMARY Caspase-11 sensing of intracellular lipopolysaccharide (LPS) plays critical roles during infections and sepsis. However, the key cell types that sense intracellular LPS and their contributions to the host responses at the organismal level are not completely clear. Here, we show that macrophage/monocyte-specific caspase-11 plays a dominant role in mediating the pathological manifestations of endotoxemia, including gasdermin D (GSDMD) activation, interleukin (IL)-1β, IL-18, and damage-associated molecular pattern (DAMP) release, tissue damage, and death. Surprisingly, caspase-11 expression in CD11c + cells and intestinal epithelial cells (IECs) plays minor detrimental roles in LPS shock. In contrast, caspase-11 expression in neutrophils is dispensable for LPS-induced lethality. Importantly, caspase-11 sensing of intracellular LPS in LyzM + myeloid cells and MRP8 + neutrophils, but not CD11c + cells and IECs, is necessary for bacterial clearance and host survival during intracellular bacterial infection. Thus, we reveal hierarchical cell-type-specific roles of caspase-11 that govern the host-protective and host-detrimental functions of the cytosolic LPS surveillance.

The Programmed Cell Death of Macrophages, Endothelial Cells, and Tubular Epithelial Cells in Sepsis-AKI

“…Activated NLRP3 forms a protein complex (NLRP3 inflammasome) consisting of NLRP3, ASC and precaspase-1, and activated caspase-1 causes macrophage pyroptosis ( 97 ). To explore how macrophages perceive intracellular LPS and function in the host at the whole body level, Kumari et al ( 98 ) constructed a conditional knockout of caspase-11 from monocytes/macrophages, neutrophils, and dendritic cells in mice, and found that macrophage/monocyte-specific caspase-11 plays a leading role in mediating the pathological manifestations of endotoxemia, including the activation of GSDMD, IL-1β and IL-18, the release of DAMPs and tissue damage, proving that caspase-11 dependent macrophage pyroptosis is pivotal in the development of sepsis.…”

Inflammasome and gasdermin signaling in neutrophils

“…Consistent with this observation, a recent study revealed that selective loss of Casp11 in Mpr8 + cells, comprising neutrophils and a small percentage of monocytes, did not protect mice from LPS‐induced caspase‐11 lethality, although caspase‐11 activity in Mpr8 + cells does appear to promote to tissue damage (Kumari et al, 2021). Instead, loss of Casp11 in endothelial cells (Cheng et al, 2017) or LysM + cells, which comprise macrophages, monocytes, and around 60% of neutrophils (Abram et al, 2014) conferred significant protection against caspase‐11‐dependent lethality (Kumari et al, 2021). Thus, inflammasome activity in neutrophils alone is unlikely to mediate immunopathology during LPS‐induced septic shock, unlike under conditions of Nlrp3 or Nlrc4 gain‐of‐function mutations (Nichols et al, 2017; Stackowicz et al, 2021).…”

“…Although multiple studies have verified that neutrophils resist pyroptosis in caspase‐1 activated cells (Chen et al, 2014; Karmakar et al, 2020; Karmakar et al, 2016; Kovacs et al, 2020; Kumari et al, 2021), emerging literature revealed that GSDMD can in fact trigger neutrophil rupture under specific conditions, indicating that these cells are not intrinsically resistant to GSDMD pores. For instance, detection of cytoplasmic LPS or Gram‐negative bacteria promotes assembly of the noncanonical inflammasome, which triggers caspase‐11 activation, robust GSDMD cleavage and neutrophil lysis (Chen et al, 2018b; Figure 3).…”

“…However, only soluble but not particulate agonists elicit NLRP3‐dependent responses in neutrophils (Chen et al, 2016). Inflammasome activation is commonly associated with maturation and secretion of the proinflammatory cytokines IL‐1β and IL‐18, however, active caspase‐1 appears to only promote robust IL‐1β but not IL‐18 secretion in murine neutrophils (Chen et al, 2014; Kumari et al, 2021; Stackowicz et al, 2021). Of note, IL‐18 was reported to be constitutively secreted by human neutrophils even in the absence of inflammasome stimulation (Bakele et al, 2014), suggesting possible species difference in IL‐18 biology between humans and mice.…”

Caspase-1-driven neutrophil pyroptosis promotes an incomplete NETosis upon Pseudomonas aeruginosa infection

“…Hence, we next infected WT or Nlrc4 -/- BMNs with various bacteria ( Salmonella Typhimurium, Shigella flexnerii, Chromobacter violaceum, Burkholderia thailandensis ) known to trigger a NLRC4 inflammasome response and monitored for cell death and IL-1β release ( Fig. 3E ) [5,28,44–46]. None of the tested bacteria triggered a significant NLRC4-dependent neutrophil lysis of murine neutrophils although they promoted NLRC4-dependent IL-1β release and Gasdermin D processing ( S2C Fig.…”