Gasdermin D in peripheral myeloid cells drives neuroinflammation in experimental autoimmune encephalomyelitis

Abstract

In this study, Li et al. demonstrate that gasdermin D in peripheral myeloid cells promotes the activation and differentiation of T cell in the secondary lymphoid organs, thus driving T cell–mediated neuroinflammation and demyelination in the CNS of EAE mice.

Gasdermins and their role in immunity and inflammation

“…From these two studies, both disulfiram and NSA reduced mortality in an LPS-induced mouse model of septic shock. Disulfiram was also found to ameliorate disease progression in EAE as described above (Li et al, 2019). Both Bay 11-7082 and disulfiram also inhibited other proteins in the pyroptotic pathway, an indicator of the lack of specificity often accompanying cysteine-modifying molecules.…”

“…While other inflammasome components such as NLRP3 and IL-1β have been previously implicated in the pathogenesis of MS and EAE, the precise role of GSDMD was not examined (Gris et al, 2010; Inoue et al, 2012). In a recent study, Li et al (2019) identified an essential role for myeloid cell GSDMD in initiating EAE. Interestingly, myeloid cell–conditional KO mice were protected from EAE as a result of impaired immune cell infiltration to the CNS, T cell activation, and demyelination.…”

Inflammasome‐associated cell death: Pyroptosis, apoptosis, and physiological implications

“…In EAE, GSDMD expressed in peripheral myeloid cells is required for the development of pathogenic Th1/Th17 cells, neuroinflammation, and disease progression. 122 These findings suggest that the development of EAE involves the induction of pyroptosis in peripheral myeloid cells, which serve as antigen-presenting cells. While allogeneic hematopoietic stem cell transplantation (HSCT) is an effective therapy for hematopoietic tumors, its beneficial effects are limited by graft-versus-host disease (GVHD).…”

Therapeutic modulation of inflammasome pathways

“…This notion is supported by empirical evidence from a host of mouse disease models that point to GSDMD-driven pyroptosis as the key driver of inflammasome-mediated pathology. 17,18,21,61,112,113 Finally, small molecule inflammasome inhibitors that can be dosed orally would relief patients from the need of lifelong injections.…”