Innate immunity to intracellular LPS

Abstract

Monitoring of the cytosolic compartment by the innate immune system for pathogen-encoded products or pathogen activities often enables the activation of a subset of caspases. In most cases, the cytosolic surveillance pathways are coupled to activation of caspase-1 via canonical inflammasome complexes. A related set of caspases, caspase-11 in rodents and caspase-4 and caspase-5 in humans, monitors the cytosol for bacterial lipopolysaccharide (LPS). Direct activation of caspase-11, caspase-4 and caspase-5 by intracellular LPS elicits the lytic cell death called 'pyroptosis', which occurs in multiple cell types. The pyroptosis is executed by the pore-forming protein GSDMD, which is activated by cleavage mediated by caspase-11, caspase-4 or caspase-5. In monocytes, formation of GSDMD pores can induce activation of the NLRP3 inflammasome for maturation of the cytokines IL-1β and IL-18. Caspase-11-mediated pyroptosis in response to cytosolic LPS is critical for antibacterial defense and septic shock. Here we review the emerging literature on the sensing of cytosolic LPS and its regulation and pathophysiological functions.

Figure 1.. Cytosolic LPS sensing by the non-canonical inflammasome.

LPS that gains access to the cytosol is sensed by a subfamily of caspases namely caspase-11 in mice and caspase-4 and caspase-5 in humans. The coordinated actions of Guanylate-binding proteins (GBPs) and immunity-related GTPase family member b10 (IRGB10) facilitate the release of LPS from bacteria in the phagosomal vacuole or those that have invaded the cytosol. Outer membrane vesicles (OMVs) secreted by bacteria also enable the cytosolic localization of LPS during infections. The type I interferon signaling initiated downstream of TLR4-TRIF recognition of LPS ensures adequate expression of non-canonical inflammasome components such as caspase-11, GBPs, and IRGB10. Active caspase-11 and caspase-4 cleave gasdermin-D (GSDMD) to liberate its N terminal domain (NTD), which migrates to the plasma membrane forming pores with an inner diameter of about 18 nm. In monocytes, the NLRP3 inflammasome is also activated following GSDMD activation most likely due to the dissipation of intracellular potassium levels through the pores. Accumulation of GSDMD pores on the plasma membrane eventually leads to pyroptotic cell death which occurs in different cell types.

Figure 2.. Negative regulation of the non-canonical inflammasome.

Host cells mitigate the pyroptotic cascade, driven by the non-canonical inflammasome downstream of cytosolic LPS, via a number of mechanisms. Glutathione peroxidase-4 (GPX4) reduces the lipid peroxidation that occurs during pyroptosis and thereby limits the extent of pyroptosis. Stearoyl lysophosphatidylcholine (LPC) can inhibit LPS binding by caspase-11. Furthermore, calcium influx elicited by the GSDMD pores leads to the activation of ESCRT-III complex, which repairs plasma membrane containing pores, thereby attenuating pyroptotic cell rupture.