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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.

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Fig. 1: Sensing of cytosolic LPS by the non-canonical inflammasome.
Fig. 2: Negative regulation of the non-canonical inflammasome.

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Acknowledgements

We thank J. Snyder for editing the manuscript. Research in the Shao laboratory is supported by the Basic Science Center Project of the National Natural Science Foundation of China (81788101) and National Key Research and Development Program of China (2016YFA0501500 and 2017YFA0505900). Research in the Rathinam laboratory is supported by the US National Institutes of Health (R01AI119015 and R21AI 135528).

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Rathinam, V.A.K., Zhao, Y. & Shao, F. Innate immunity to intracellular LPS. Nat Immunol 20, 527–533 (2019). https://doi.org/10.1038/s41590-019-0368-3

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