Irgm2 and Gate-16 put a break on caspase-11 activation

Abstract

In infections caused by gram-negative bacteria, the bacterial cell wall component lipopolysaccharide (LPS) acts as a potent pathogen-associated molecular pattern (PAMP) that triggers the innate immune system. This is accomplished by two pattern recognition receptor systems. Toll-like receptor 4 (TLR4) senses extracellular LPS and induces a broad pro-inflammatory transcriptional program and also antiviral interferons. A complementary system detects intracellular LPS. As such, upon its release into the cytoplasm, LPS can directly engage the protease caspase-4 (caspase-11 in the murine system) and thereby trigger a pro-inflammatory cell death program known as pyroptosis (Rathinam et al, 2019). This is mediated by active caspase-4 cleaving its substrate gasdermin D (GSDMD). The thereby released N-terminal fragment of GSDMD inserts into the cell membrane and forms a cytotoxic pore. As a consequence, the cell ruptures and releases its pro-inflammatory content. In addition, the GSDMD pore results in potassium efflux that can activate the NLRP3 inflammasome. NLRP3 in turn activates caspase-1, which matures pro-IL-1β and pro-IL-18, further perpetuating the inflammatory nature of this cell death. Given its unconventional mode of NLRP3 activation, this pathway has been coined the non-canonical inflammasome.

Figure 1. Irgm2 and Gate‐16 fine‐tune the immune response to gram‐negative bacteria

Lipopolysaccharides (LPS) from gram‐negative bacteria or bacterial‐derived outer membrane vesicles (OMVs) prime macrophages to induce type‐I‐Interferon (IFN‐I) via toll‐like receptor 4 (TLR4). Subsequently, IFN‐I induces host factors such as GBP‐proteins or Irgm2 and Gate‐16. In parallel, bacteria and OMVs that have been phagocytosed are liberated from the phago‐lysosome to the cytoplasm, where GBPs facilitate the recognition of LPS by caspase‐11. The newly identified factors Irgm2 (in mice) and Gate‐16 (in mice and humans) restrict the activation of caspase‐11. In Irgm2‐deficient cells, activation of caspase‐11 can even occur in the absence of GBPs encoded on chromosome 3. On the organismal level, the enhanced activation of caspase‐11 in the absence of Irgm2 translates into an overshooting immune response resulting in septic shock and death of the host. Therefore, Irgm2 and Gate‐16 fine‐tune the immune response to gram‐negative bacteria.