Caspase-11 non-canonical inflammasome: a critical sensor of intracellular lipopolysaccharide in macrophage-mediated inflammatory responses - PubMed (original) (raw)

Intracellular

LPS

‐mediated caspase‐4/5/11 non‐canonical inflammasome activation. (a)

LPS

‐containing

OMV

s derived from Gram‐negative bacteria is internalized into a macrophage by endocytosis, and (b)

LPS

of the

OMV

s is released into the cytoplasm from the Gram‐negative bacterium‐containing vacuole by

GBP

chr3‐mediated lysis. (c) The released intracellular

LPS

binds directly to pro‐caspase‐11 and to pro‐caspase‐4/5/11

CARD

motifs through the lipid A moiety, (d) leading to oligomerization of pro‐caspase‐4/5/11 to induce non‐canonical inflammasome activation. (e) Active caspase‐4/5/11 non‐canonical inflammasome activates the

NLRP

3 canonical inflammasome via an unknown mechanism, (f) inducing the proteolysis and maturation of pro‐caspase‐1. (g) Cleaved active caspase‐1, in turn, induces the proteolysis and maturation of the pro‐inflammatory cytokines

‐1_β_ and

‐18. (h) Active caspase‐4/5/11 non‐canonical inflammasomes also cleave the linker loop of intact

GSDMD

to generate N‐ and C‐terminal fragments of

GSDMD

. (i) The cleaved N‐terminal fragments of

GSDMD

are localized to the cell membrane, bind to phosphoinositides of the cell membrane, and oligomerize to form membrane pores, resulting in cell swelling and lysis, known as pyroptosis. (j) Proteolysed mature

‐1_β_ and

‐18 are secreted through

GSDMD

pores. Abbreviations used:

OMV

, outer membrane vesicle; Caspase, cysteine‐aspartic protease;

GBP

, guanylate‐binding protein; immunity‐related

GTP

ase family member b10,

IRGB

10;

LPS

, lipopolysaccharide;

GSDMD

, gasdermin D;

, interleukin; N, N‐terminal fragment of

GSDMD

; C, C‐terminal fragment of

GSDMD

;

CARD

, caspase recruit domain;

NACHT

, nucleotide‐binding and oligomerization domain;

PYD

, pyrin domain.