This is the first study to demonstrate that the active form of GSDM-D is found exclusively in the circulation of septic critically ill patients raising its potential as an agent of dysregulated immunity in systemic infection.

This is a significant expansion over limited work in our own laboratory that had detected circulating active GSDM-D in association with active caspase 1 while investigating caspase 1 mediated pyroptosis in seven patients with ARDS.

The significant positive correlation between active GSDM-D and CD63 (exosome marker), CD14 (monocyte marker), and CD69 (marker of activated monocytes) lead us to conclude that the circulating active GSDM-D in septic patients is encapsulated in exosomes that originate from activated monocytes.

There are several limitations of this study. Although the mechanistic role of GSDM-D in pyroptosis and cell injury has been well described in vitro, the identification of circulating active GSDM-D in septic patients is mostly correlative.

Second, we did not assess the kinetics of expression of GSDM-D throughout the evolution of the septic syndrome.

Current ongoing work in the laboratory is focused on longitudinal analysis of GSDM-D levels in our critically ill patient population.

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