Neutrophil Caspase-11 Is Essential to Defend against a Cytosol-Invasive Bacterium

Abstract

SUMMARY Either caspase-1 or caspase-11 can cleave gasdermin D to cause pyroptosis, eliminating intracellular replication niches. We previously showed that macrophages detect Burkholderia thailandensis via NLRC4, triggering the release of interleukin (IL)-18 and driving an essential interferon (IFN)-γ response that primes caspase-11. We now identify the IFN-γ-producing cells as a mixture of natural killer (NK) and T cells. Although both caspase-1 and caspase-11 can cleave gasdermin D in macrophages and neutrophils, we find that NLRC4-activated caspase-1 triggers pyroptosis in macrophages, but this pathway does not trigger pyroptosis in neutrophils. In contrast, caspase-11 triggers pyroptosis in both macrophages and neutrophils. This translates to an absolute requirement for caspase-11 in neutrophils during B. thailandensis infection in mice. We present an example of inflammasome sensors causing diverging outcomes in different cell types. Thus, cell fates are dictated not simply by the pathogen or inflammasome, but also by how the cell is wired to respond to detection events.

RIPK1 activates distinct gasdermins in macrophages and neutrophils upon pathogen blockade of innate immune signalling

“…Since RIPK1 kinase activity in myeloid cells drives anti-Yersinia defence (20), it is possible that GSDME may also promote pyroptosis and bioactive IL-1b release from infected inflammatory monocytes. Given that gasdermin cleavage elicits distinct functional outcomes in different myeloid cell subsets (12,29,32,33), future studies characterising the regulation and biological function of gasdermins in monocytes will be of interest. One potential caveat of our study, however, is the sensitivity between murine and human myeloid cells to Yersinia infection.…”

“…4A). Since GSDMD activation does not universally trigger pyroptosis in neutrophils (12,29,32,33), we next investigated the cleavage status of neutrophil GSDMD upon Yptb infection. WT and Caspase-1/11 -/neutrophils were challenged with Yptb or a Salmonella DsifA mutant, which triggers robust caspase-11-dependent GSDMD cleavage, as a positive control (12).…”

Neutrophils: Many Ways to Die

“…This can suggest that neutrophils do not undergo pyroptosis in response to proteins of some intracellular pathogens (such as flagellin or the proteins making up T3SS) that activate assembly of NLRC4 inflammasome. However, it has been determined that neutrophils can undergo pyroptosis, activating a non-canonical infammasome pathway through P2X7 receptors in absence of NOX2 in pseudomonal infections ( 105 , 123 , 124 ).…”

NET formation – mechanisms and how they relate to other cell death pathways

“…In contrast to the above-mentioned findings, murine neutrophils are resistant to pyroptosis downstream of canonical inflammasome activation. While these cells express inflammasome components and are able to release active IL-1b, unlike macrophages they do not die by pyroptosis [92,[95][96][97]. Several mechanisms could contribute to this resistance.…”

“…However, ESCRT-dependent membrane repair reduced pyroptotic lysis both upon canonical and noncanonical inflammasome activation [99]. Neutrophils preferentially resist pyroptosis in the context of canonical inflammasome activation [92,[95][96][97], and it is not clear how ESCRT-mediated repair would discriminate between the two activation pathways in neutrophils but not in macrophages. Neutrophils might express less caspase-4/-11 than macrophages, and therefore have a reduced potential to activate GSDMD activity or neutrophil caspase-1 might be less efficient in processing GSDMD than caspase-4/-11 [92].…”