Inflammatory caspases are innate immune receptors for intracellular LPS

  title={Inflammatory caspases are innate immune receptors for intracellular LPS},
  author={Jianjin Shi and Yue Zhao and Yupeng Wang and Wenqing Gao and Jingjin Ding and Peng Li and Liyan Hu and Feng Shao},
The murine caspase-11 non-canonical inflammasome responds to various bacterial infections. Caspase-11 activation-induced pyroptosis, in response to cytoplasmic lipopolysaccharide (LPS), is critical for endotoxic shock in mice. The mechanism underlying cytosolic LPS sensing and the responsible pattern recognition receptor are unknown. Here we show that human monocytes, epithelial cells and keratinocytes undergo necrosis upon cytoplasmic delivery of LPS. LPS-induced cytotoxicity was mediated by… 

Non-canonical activation of inflammatory caspases by cytosolic LPS in innate immunity.

Innate immunity to intracellular LPS

The emerging literature on the sensing of cytosolic LPS and its regulation and pathophysiological functions is reviewed, finding mechanisms for the recognition of intracellular lipopolysaccharide and its essential role in responses to Gram-negative bacteria are described.

Lipopolysaccharide Recognition in the Crossroads of TLR4 and Caspase-4/11 Mediated Inflammatory Pathways

The LPS-induced TLR4 and caspase-4/11 mediated signaling pathways and their cross-talk are described and specific structural features of the lipid A motif of diverse LPS variants that have been reported to activate caspases or to induced activation of NLRP3 inflammasome are scrutinized.

The oxidized phospholipid oxPAPC protects from septic shock by targeting the non-canonical inflammasome in macrophages

OxPAPC and its derivatives might provide a basis for therapies that target non-canonical inflammasomes during Gram-negative bacterial sepsis and consequently inhibits LPS-induced pyroptosis, IL-1β release and septic shock.

Cytosolic Sensor of Bacterial Lipopolysaccharide in Human Macrophages

It is found that in response to infection by each of several gram-negative intracellular bacterial pathogens or to LPS transfection, efficient activation of the non-canonical pathway in human-derived macrophages depends on NLRP11, a previously missing link in the human non- canonical inflammasome activation pathway.

Caspase-4 disaggregates lipopolysaccharide micelles via LPS-CARD interaction

The overexpression and purification of monomeric caspase-4 (C258A) and CARD domain from E. coli are reported and it is demonstrated that purified caspases bind large LPS micelles and disaggregate them to small complexes.

Dynamin-related Irgm proteins modulate LPS-induced caspase-4 activation and septic shock

Dynamin-related membrane remodeling proteins belonging to the family of Immunity related GTPases M clade (IRGM) are identified as negative regulators of caspase-4 activation in macrophages, indicating that dysregulated Irgm isoform expression disrupts intracellular LPS processing pathways that limit LPS availability for casp enzyme activation.

Dimerization and auto-processing induce caspase-11 protease activation within the non-canonical inflammasome

It is shown that caspase-11 dimerization is necessary and sufficient for eliciting basal casp enzyme-11 protease function, such as the ability to auto-cleave, and self-cleavage at the D285 site is required to generate the fully active caspasing- 11 protease that mediates gasdermin D cleavage, macrophage death, and NLRP3-dependent IL-1β production.

Human caspase-4 detects tetra-acylated LPS and cytosolic Francisella and functions differently from murine caspase-11

The data demonstrate a broader reactivity of caspase-4 to under-acylated LPS than caspases-11, which may have important clinical implications for management of sepsis, and establishes that human Guanylate-binding proteins promote inflammasome responses toUnder-acylation LPS.



Cytoplasmic LPS Activates Caspase-11: Implications in TLR4-Independent Endotoxic Shock

It is reported that contamination of the cytoplasm by lipopolysaccharide (LPS) is the signal that triggers caspase-11 activation in mice, and this data reveal a new pathway for detecting cy toplasmic LPS.

Caspase-11 increases susceptibility to Salmonella infection in the absence of caspase-1

It is shown that non-canonical caspase-11 activation contributes to macrophage death during S. typhimurium infection, indicating that caspases-11-dependent cell death is detrimental to the host in the absence of caspasing-1-mediated innate immunity, resulting in extracellular replication of a facultative intracellular bacterial pathogen.

Noncanonical Inflammasome Activation by Intracellular LPS Independent of TLR4

It is shown that macrophages loaded with synthetic lipid A, E. coli lipopolysaccharide (LPS), or S. typhimurium LPS activate caspase-11 independently of the LPS receptor Toll-like receptor 4 (TLR4), revealing a TLR4-independent mechanism for innate immune recognition of LPS.

Guanylate binding proteins promote caspase-11–dependent pyroptosis in response to cytoplasmic LPS

It is demonstrated that IFN-inducible guanylate binding protein (Gbp) proteins stimulate caspase-11–dependent, cell-autonomous immunity in response to cytoplasmic LPS, and a role is suggested for Gbpchr3 proteins in the detection of cy toplasmo LPS and the activation of the noncanonical inflammasome.

Caspase-11 Protects Against Bacteria That Escape the Vacuole

It is reported that caspase-11 is required for innate immunity to cytosolic, but not vacuolar, bacteria and is critical for surviving exposure to ubiquitous environmental pathogens.

Caspase-11 activation requires lysis of pathogen-containing vacuoles by IFN-induced GTPases

It is reported that a cluster of small interferon-inducible GTPases, the so-called guanylate-binding proteins, is required for the full activity of the non-canonical caspase-11 inflammasome during infections with vacuolar Gram-negative bacteria.

Non-canonical inflammasome activation targets caspase-11

It is shown, with C57BL/6 Casp11 gene-targeted mice, that caspase-11 is critical for casp enzyme-1 activation and IL-1β production in macrophages infected with Escherichia coli, Citrobacter rodentium or Vibrio cholerae, and a unique pro-inflammatory role for casingase- 11 in the innate immune response to clinically significant bacterial infections is highlighted.

Caspase-11 stimulates rapid flagellin-independent pyroptosis in response to Legionella pneumophila

Data indicate that macrophages respond to microbial signatures to produce proteins that mediate a capsase- 11 response and that the caspase-11 system provides an alternative pathway for rapid detection of an intracellular pathogen capable of evading the canonical casp enzyme-1 activation system that responds to bacterial flagellin.