ABSTRACT
Gasdermins have been identified as playing a prominent role in the innate immune response as the executors of a specific type of cell death called pyroptosis. Specific proteolytic cleavage of gasdermins generates an N-terminal that oligomerizes and forms pores in the cell membrane. Although pyroptosis has been widely described in mammals, the importance of gasdermins and gasdermin-like proteins in inducing cell death in other vertebrates, in invertebrates and in other taxa including fungi and bacteria is still being determined. Mammalian, fungal and bacterial gasdermins have in common the fact that they go through the same stages (such as proteolytic activation) when inducing membrane rupture, which suggests that pyroptosis is as an ancient mechanism. In this review, we summarize the evolution and function of the gasdermin and gasdermin-like proteins in animals, fungi and bacteria.
ABSTRACT
The Hedgehog (Hh) pathway is essential for the embryonic development and homeostatic maintenance of many adult tissues and organs. It has also been associated with some functions of the innate and adaptive immune system. However, its involvement in the immune response has not been well determined. Here we study the role of Hh signalling in the modulation of the immune response by using the Ptch-1-LacZ+/- mouse model (hereinafter referred to as ptch+/-), in which the hemizygous inactivation of Patched-1, the Hh receptor gene, causes the constitutive activation of Hh response genes. The in vitro TCR stimulation of spleen and lymph node (LN) T cells showed increased levels of Th2 cytokines (IL-4 and IL-10) in ptch+/-cells compared to control cells from wild-type (wt) littermates, suggesting that the Th2 phenotype is favoured by Hh pathway activation. In addition, CD4+ cells secreted less IL-17, and the establishment of the Th1 phenotype was impaired in ptch+/- mice. Consistently, in response to an inflammatory challenge by the induction of experimental autoimmune encephalomyelitis (EAE), ptch+/- mice showed milder clinical scores and more minor spinal cord damage than wt mice. These results demonstrate a role for the Hh/ptch pathway in immune response modulation and highlight the usefulness of the ptch+/- mouse model for the study of T-cell-mediated diseases and for the search for new therapeutic strategies in inflammatory diseases.
