Extracellular ATP Activates the NLRP3 Inflammasome and Is an Early Danger Signal of Skin Allograft Rejection

Immune cells are equipped with a number of receptors that recognize sterile injury and pathogens. We find that host immune cells release ATP as an inflammatory signal in response to allogeneic transplantation. ATP then acts via a feedback mechanism on the P2X7 channel to activate the NLRP3 inflammasome and subsequently process and release interleukin (IL)-18. This process is a necessary stage in the deleterious Th1 response against allotransplantation via interferon-γ production. Lack of IL-18 resulted in a decrease in graft-infiltrating CD8 cells but an increase in regulatory T cells. In human liver transplant patients undergoing progressive immunosuppressive drug withdrawal, we found that patients experiencing acute rejection had higher levels of the P2X7 receptor in circulating inflammatory monocytes compared to tolerant patients. These data suggest that the pharmacological inhibition of the P2X7 receptor or the NLRP3 inflammasome will aid in inducing transplant tolerance without complete immunoparalysis. Amores-Iniesta et al. find that extracellular ATP is important in the establishment of allograft rejection during mismatched tissue transplantation through NLRP3 inflammasome activation and IL-18 production. The P2X7 receptor in macrophages helps to maintain high extracellular ATP levels in mismatched tissue grafts at early time points after transplantation

Microbial responses to changes in flow status in temporary headwater streams: a cross-system comparison

Microbial communities are responsible for the bulk of biogeochemical processing in temporary headwater streams, yet there is still relatively little known about how community structure and function respond to periodic drying. Moreover, the ability to sample temporary habitats can be a logistical challenge due to the limited capability to measure and predict the timing, intensity and frequency of wet-dry events. Unsurprisingly, published datasets on microbial community structure and function are limited in scope and temporal resolution and vary widely in the molecular methods applied. We compared environmental and microbial community datasets for permanent and temporary tributaries of two different North American headwater stream systems: Speed River (Ontario, Canada) and Parkers Creek (Maryland, USA). We explored whether taxonomic diversity and community composition were altered as a result of flow permanence and compared community composition amongst streams using different 16S microbial community methods (i.e., T-RFLP and Illumina MiSeq). Contrary to our hypotheses, and irrespective of method, community composition did not respond strongly to drying. In both systems, community composition was related to site rather than drying condition. Additional network analysis on the Parkers Creek dataset indicated a shift in the central microbial relationships between temporary and permanent streams. In the permanent stream at Parkers Creek, associations of methanotrophic taxa were most dominant, whereas associations with taxa from the order Nitrospirales were more dominant in the temporary stream, particularly during dry conditions. We compared these results with existing published studies from around the world and found a wide range in community responses to drying. We conclude by proposing three hypotheses that may address contradictory results and, when tested across systems, may expand understanding of the responses of microbial communities in temporary streams to natural and human-induced fluctuations in flow-status and permanence