Following traumatic brain injury (TBI), individuals over 65 years of age show increased mortality and worse functional outcomes compared to younger persons. As neuroinflammation is a key pathobiological mechanism of secondary injury after TBI, we examined how aging affects posttraumatic microglial responses and functional outcomes. Young (12-week-old) and aged (18month-old) male C57Bl/6 mice were subjected to moderate-level controlled cortical impact (CCI) or sham surgery and neurological function was evaluated. At 72 hours post-injury, brain, blood, and spleen leukocyte counts were assessed ex vivo using flow cytometry. Aged mice demonstrated more severe deficits in forelimb grip strength, balance and motor coordination, spontaneous locomotor activity, and anxiety-like behavior. These animals also exhibited more robust microglial proliferation and significantly higher numbers of brain-infiltrating leukocytes. Microglia in aged mice showed impairments in phagocytic activity and higher production of interleukin-1β (IL-1β). Infiltrating myeloid cells in aged TBI mice also had deficits in phagocytosis, but showed diminished pro-inflammatory cytokine production and greater reactive oxygen species production. Expression of several senescence markers (Bcl-2, p16 ink4a , p21 cip1a , lipofuscin, and H2AX (pS139)) was increased with age and/or TBI in both microglia and injured cortex. Although there was no difference in the number of circulating blood neutrophils as a function of age, young mice exhibited more pronounced TBI-induced splenomegaly and splenic myeloid cell expansion. Thus,

Micro-RNAs (miRs) are short, noncoding RNAs that negatively regulate gene expression at the post-transcriptional level and have been implicated in the pathophysiology of secondary damage after traumatic brain injury (TBI). Among miRs linked to inflammation, miR-155 has been implicated as a pro-inflammatory factor in a variety of organ systems. We examined the expression profile of miR-155, following experimental TBI (controlled cortical impact) in adult male C57Bl/6 mice, as well as the effects of acute or delayed administration of a miR-155 antagomir on post-traumatic neuroinflammatory responses and neurological recovery. Trauma robustly increased miR-155 expression in the injured cortex over 7 days. Similar TBI-induced miR-155 expression changes were also found in microglia/macrophages isolated from the injured cortex at 7 days post-injury. A miR-155 hairpin inhibitor (antagomir; 0.5 nmol), administered intracerebroventricularly (ICV) immediately after injury, attenuated neuroinflammatory markers at both 1 day and 7 days post-injury and reduced impairments in spatial working memory. Delayed ICV infusion of the miR-155 antagomir (0.5 nmol/day), beginning 24 h post-injury and continuing for 6 days, attenuated neuroinflammatory markers at 7 days post-injury and improved motor, but not cognitive, function through 28 days. The latter treatment limited NADPH oxidase 2 expression changes in microglia/macrophages in the injured cortex and reduced cortical lesion volume. In summary, TBI causes a robust and persistent neuroinflammatory response that is associated with increased miR-155 expression in microglia/macrophages, and miR-155 inhibition reduces post-traumatic neuroinflammatory responses and improves neurological recovery. Thus, miR-155 may be a therapeutic target for TBI-related neuroinflammation.

Women who have experienced adverse childhood events (ACEs) around puberty are at the greatest risk for neuropsychiatric disorders across the lifespan. This population is exceptionally vulnerable to neuropsychiatric disease presentation during the hormonally dynamic state of pregnancy. We previously established that chronic adversity around puberty in female mice significantly altered their HPA axis function specifically during pregnancy, modeling the effects of pubertal ACEs we also reported in women. We hypothesized that the pregnancy hormone, allopregnanolone, was involved in presentation of the blunted stress response phenotype by its interaction with the molecular programming that had occurred during pubertal adversity experience. Here, in adult mice previously stressed during puberty, allopregnanolone administration was sufficient to reproduce the decreased corticosterone response after acute stress. Examination of neuronal activation and the electrophysiological properties of CRF neurons in the paraventricular nucleus of the hypothalamus (PVN) found no significant changes in synaptic function that corresponded with the blunted HPA axis reactivity. However, at the chromatin level, utilization of ATAC-Seq profiling demonstrated a dramatic remodeling of DNA accessibility in the PVN following pubertal adversity. Altogether, these data establish a potential molecular mechanism whereby adversity during puberty can enact lasting transcriptional control that manifests only during a unique period of the lifespan where dynamic hormonal changes occur. These results highlight a biological process that may impart an increased risk for a highly vulnerable population, whereby pubertal programming of the PVN results in aberrant HPA axis responsiveness when exposed to the hormonal changes unique to pregnancy.

No abstract

Chronic alcohol consumption is linked to the development of alcohol-associated liver disease (ALD). This disease is characterized by a clinical spectrum ranging from steatosis to hepatocellular carcinoma. Several cell types are involved in ALD progression, including hepatic macrophages. Kupffer cells (KCs) are the resident macrophages of the liver involved in the progression of ALD by activating pathways that lead to the production of cytokines and chemokines. In addition, KCs are involved in the production of reactive oxygen species. Reactive oxygen species are linked to the induction of oxidative stress and inflammation in the liver. These events are activated by the bacterial endotoxin, lipopolysaccharide, that is released from the gastrointestinal tract through the portal vein to the liver. Lipopolysaccharide is recognized by receptors on KCs that are responsible for triggering several pathways that activate proinflammatory cytokines involved in alcohol-induced liver injury. In addition, KCs activate hepatic stellate cells that are involved in liver fibrosis. Novel strategies to treat ALD aim at targeting Kupffer cells. These interventions modulate Kupffer cell activation or macrophage polarization. Evidence from mouse models and early clinical studies in patients with ALD injury supports the notion that pathogenic macrophage subsets can be successfully translated into novel treatment options for patients with this disease.