Beneficial islet inflammation in health depends on pericytic TLR/MyD88 signaling.

While inflammation is beneficial for insulin secretion during homeostasis, its transformation adversely affects ß-cells and contributes to diabetes. However, the regulation of islet inflammation for maintaining glucose homeostasis remains largely unknown. Here, we identified pericytes as pivotal regulators of islet immune and ß-cell function in health. Islets and pancreatic pericytes express various cytokines in healthy humans and mice. To interfere with the pericytic inflammatory response, we selectively inhibited the TLR/MyD88 pathway in these cells in transgenic mice. The loss of MyD88 impaired pericytic cytokine production. Furthermore, MyD88-deficient mice exhibited skewed islet inflammation with fewer cells, an impaired macrophage phenotype, and reduced IL-1ß production. This aberrant pericyte-orchestrated islet inflammation was associated with ß-cell dedifferentiation and impaired glucose response. Additionally, we found that Cxcl1, a pericytic MyD88-dependent cytokine, promoted immune IL-1ß production. Treatments with either Cxcl1 or IL-1ß restored the mature ß-cell phenotype and glucose response in transgenic mice, suggesting a potential mechanism through which pericytes and immune cells regulate glucose homeostasis. Our study revealed pericyte-orchestrated islet inflammation as a crucial element in glucose regulation, implicating this process as a potential therapeutic target for diabetes.

Gaseous nitric oxide tumor ablation induces an anti-tumor abscopal effect.

BACKGROUND: In-situ tumor ablation provides the immune system with the appropriate antigens to induce anti-tumor immunity. Here, we present an innovative technique for generating anti-tumor immunity by delivering exogenous ultra-high concentration (> 10,000 ppm) gaseous nitric oxide (UHCgNO) intratumorally. METHODS: The capability of UHCgNO to induce apoptosis was tested in vitro in mouse colon (CT26), breast (4T1) and Lewis lung carcinoma (LLC-1) cancer cell lines. In vivo, UHCgNO was studied by treating CT26 tumor-bearing mice in-situ and assessing the immune response using a Challenge assay. RESULTS: Exposing CT26, 4T1 and LLC-1 cell lines to UHCgNO for 10 s-2.5 min induced cellular apoptosis 24 h after exposure. Treating CT26 tumors in-situ with UHCgNO followed by surgical resection 14 days later resulted in a significant secondary anti-tumor effect in vivo. 100% of tumor-bearing mice treated with 50,000 ppm UHCgNO and 64% of mice treated with 20,000 ppm UHCgNO rejected a second tumor inoculation, compared to 0% in the naive control for 70 days. Additionally, more dendrocytes infiltrated the tumor 14 days post UHCgNO treatment versus the nitrogen control. Moreover, T-cell penetration into the primary tumor was observed in a dose-dependent manner. Systemic increases in T- and B-cells were seen in UHCgNO-treated mice compared to nitrogen control. Furthermore, polymorphonuclear-myeloid-derived suppressor cells were downregulated in the spleen in the UHCgNO-treated groups. CONCLUSIONS: Taken together, our data demonstrate that UHCgNO followed by the surgical removal of the primary tumor 14 days later induces a strong and potent anti-tumor response.

Short-range quorum sensing controls horizontal gene transfer at micron scale in bacterial communities.

In bacterial communities, cells often communicate by the release and detection of small diffusible molecules, a process termed quorum-sensing. Signal molecules are thought to broadly diffuse in space; however, they often regulate traits such as conjugative transfer that strictly depend on the local community composition. This raises the question how nearby cells within the community can be detected. Here, we compare the range of communication of different quorum-sensing systems. While some systems support long-range communication, we show that others support a form of highly localized communication. In these systems, signal molecules propagate no more than a few microns away from signaling cells, due to the irreversible uptake of the signal molecules from the environment. This enables cells to accurately detect micron scale changes in the community composition. Several mobile genetic elements, including conjugative elements and phages, employ short-range communication to assess the fraction of susceptible host cells in their vicinity and adaptively trigger horizontal gene transfer in response. Our results underscore the complex spatial biology of bacteria, which can communicate and interact at widely different spatial scales.