Traumatic brain injury (TBI) is a leading global cause of death and disability. Here we demonstrate in an experimental mouse model of TBI that mild forms of brain trauma cause severe deficits in meningeal lymphatic drainage that begin within hours and last out to at least one month post-injury. To investigate a mechanism underlying impaired lymphatic function in TBI, we examined how increased intracranial pressure (ICP) influences the meningeal lymphatics. We demonstrate that increased ICP can contribute to meningeal lymphatic dysfunction. Moreover, we show that pre-existing lymphatic dysfunction before TBI leads to increased neuroinflammation and negative cognitive outcomes. Finally, we report that rejuvenation of meningeal lymphatic drainage function in aged mice can ameliorate TBI-induced gliosis. These findings provide insights into both the causes and consequences of meningeal lymphatic dysfunction in TBI and suggest that therapeutics targeting the meningeal lymphatic system may offer strategies to treat TBI.

Background & Aims Chronic hepatitis affects phenotypes of innate and adaptive immune cells. Mucosal associated invariant T (MAIT) cells are enriched in the liver as compared to the blood, respond to intra-hepatic cytokines, and (via the semi-invariant T-cell receptor) to bacteria translocated from the gut. Little is known about the role of MAIT cells in livers of patients with chronic hepatitis C virus (HCV) infection and their fate after antiviral therapy. Methods We collected blood samples from 42 patients with chronic HCV infection who achieved a sustained virologic response after 12 weeks of treatment with sofosbuvir and velpatasvir. Mononuclear cells were isolated from blood before treatment, at weeks 4 and 12 during treatment, and 24 weeks after the end of treatment. Liver biopsies were collected from 37 of the patients prior to and at week 4 of treatment. Mononuclear cells from 56 blood donors and 10 livers that were not suitable for transplantation were used as controls. Liver samples were assessed histologically for inflammation and fibrosis. Mononuclear cells from liver and blood were studied by flow cytometry and analyzed for responses to cytokine and bacterial stimulation. Results The frequency of MAIT cells among T cells was significantly lower in blood and liver samples of patients with HCV infection than of controls (median 1.31% vs 2.32% for blood samples, P=.0048 and median 4.34% vs 13.40% for liver samples, P=.001). There was an inverse correlation between the frequency of MAIT cells in the liver and histologically determined levels of liver inflammation (r=−.5437, P=.0006) and fibrosis (r=−.5829, P=.0002). MAIT cells from the liver had higher levels of activation and cytotoxicity than MAIT cells from blood (P<.0001). Production of interferon gamma (IFNG) by MAIT cells was dependent on monocyte-derived interleukin 18 (IL18), and was reduced in patients with HCV infection in response to T-cell receptor-mediated but not cytokine-mediated stimulation, as compared to controls. Anti-viral therapy rapidly decreased liver inflammation and MAIT cell activation and cytotoxicity, and increased the MAIT cell frequency among intra-hepatic but not blood T cells. The MAIT cell response to T-cell receptor-mediated stimulation did not change during the 12 weeks of antiviral therapy. Conclusions In analyses of paired blood and liver samples from patients with chronic HCV infection before, during and after antiviral therapy with sofosbuvir and velpatasvir, we found that intrahepatic MAIT cells are activated by monocyte-derived cytokines and depleted in HCV-induced liver inflammation.

Neurodevelopment is characterized by rapid rates of neural cell proliferation and differentiation followed by a period of massive cell death where over half of all recently generated brain cells are pruned back. Large amounts of DNA damage, cellular debris, and byproducts of cellular stress are generated during these neurodevelopmental events, all of which can potentially activate immune signaling. How the immune response to this collateral damage influences brain maturation and function currently remains poorly understood. Here we show that the AIM2 inflammasome contributes to proper brain development and that disruptions in this immune sensor of genotoxic stress lead to behavioral abnormalities. The AIM2 inflammasome has been most extensively studied in the context of infection, where its activation in response to double-stranded DNA (dsDNA) is known to trigger cytokine production as well as a Gasdermin-D-mediated form of cell death commonly referred to as pyroptosis 1-4 . We observe pronounced AIM2 inflammasome activation in neurodevelopment and find that defects in this DNA damage surveillance sensor result in anxiety-related behaviors. We further show that the AIM2 inflammasome contributes to central nervous system (CNS) homeostasis specifically through its regulation of the cell death executioner Gasdermin-D, and not via its involvement in IL-1 and/or IL-18 production. Consistent with a role for this sensor of genomic stress in the purging of genetically compromised CNS cells, we find that defective AIM2 inflammasome signaling results in decreased neural cell death both in response to DNA damage-inducing agents and during neurodevelopment. Moreover, we report that

Recent studies suggest that autism is often associated with dysregulated immune responses and altered microbiota composition. This has led to growing speculation about potential roles for hyperactive immune responses and the microbiome in autism. Yet how microbiome-immune cross-talk contributes to neurodevelopmental disorders currently remains poorly understood. In this study, we report critical roles for prenatal microbiota composition in the development of behavioral abnormalities in a murine maternal immune activation (MIA) model of autism that is driven by the viral mimetic polyinosinic-polycytidylic acid. We show that preconception microbiota transplantation can transfer susceptibility to MIA-associated neurodevelopmental disease and that this is associated with modulation of the maternal immune response. Furthermore, we find that ablation of IL-17a signaling provides protection against the development of neurodevelopmental abnormalities in MIA offspring. Our findings suggest that microbiota landscape can influence MIA-induced neurodevelopmental disease pathogenesis and that this occurs as a result of microflora-associated calibration of gestational IL-17a responses.