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Abstract Chronic psychosocial stress induced by the chronic subordinate colony housing (CSC, 19 Days) paradigm promotes functional splenic in vitro glucocorticoid (GC) resistance, but only if associated with significant bite wounding or prior abdominal transmitter implantation. Moreover, sensory contact to social defeat of conspecifics represents a social stressor for the observer individual. As the occurence and severity of bite wounding is not adequately controllable, the present study aimed to develop an animal model, allowing a bite wound-independent, more reliable generation of chronically-stressed mice characterized by functional splenic in vitro GC resistance. Therefore, male C57BL/6N mice received a standardized sterile intraperitoneal (i.p.) incision surgery or SHAM treatment one week prior to 19-days of (i) CSC, (ii) witnessing social defeat during CSC exposure in sensory contact (SENS) or (iii) single-housing for control (SHC), before assessing basal and LPS-induced splenic in vitro cell viability and GC resistance. Our results indicate that individually-housed SENS but not CSC mice develop mild signs of splenic in vitro GC resistance, when undergoing prior i.p.-wounding. Taken together and considering that future studies are warranted, our findings support the hypothesis that the combination of repeated standardized i.p.-wounding with chronic sensory stress exposure represents an adequate tool to induce functional splenic in vitro GC resistance independent of the occurrence of uncontrollable bite wounds required in social stress paradigms to induce a comparable phenotype.

Abstract Mental traumatization is associated with long-bone growth retardation, osteoporosis and increased fracture risk. We revealed earlier that mental trauma disturbs cartilage-to-bone transition during bone growth and repair in mice. Trauma increased tyrosine hydroxylase-expressing neutrophils in bone marrow and fracture callus. Here we show that tyrosine hydroxylase expression in the fracture hematoma of patients correlates positively with acknowledged stress, depression, and pain scores as well as individual ratings of healing-impairment and pain-perception post-fracture. Moreover, mice lacking tyrosine hydroxylase in myeloid cells are protected from chronic psychosocial stress-induced disturbance of bone growth and healing. Chondrocyte-specific β2-adrenoceptor-deficient mice are also protected from stress-induced bone growth retardation. In summary, our preclinical data identify locally secreted catecholamines in concert with β2-adrenoceptor signalling in chondrocytes as mediators of negative stress effects on bone growth and repair. Given our clinical data, these mechanistic insights seem to be of strong translational relevance.

Abstract Ex vivo culturing of isolated PBMCs from individuals vaccinated with the coronavirus disease 2019 (COVID-19) vaccine BNT162b1 revealed a pronounced T cell response in the presence of the receptor binding domain (RBD) of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike protein. The latter was 10-fold more pronounced than the ex vivo response of PBMCs from the same individuals to other common pathogen T cell epitope pools, suggesting COVID-19 vaccination to induce RBD-specific T cell responses and not to facilitate T cell (re)activity in general. In the current study we investigated whether COVID-19 vaccination long-lastingly affects plasma interleukin (IL)-6 concentrations, complete blood counts, ex vivo IL-6 and IL-10 secretion of PBMCs cultured under basal conditions or in the presence of concanavalin (Con) A and lipopolysaccharide (LPS), salivary cortisol and α-amylase, mean arterial pressure (MAP), heart rate (HR) as well as mental and physical health status. The study was initially designed to investigate whether the presence vs. absence of own pets during urban upbringing has protective effects against psychosocial stress-induced immune activation during adulthood. However, as COVID-19 vaccines were approved while the study was ongoing and as, therefore, both vaccinated and non-vaccinated individuals have been recruited, we were able to stratify our data set with respect to the COVID-19 vaccination status and to assess the long-lasting effects of COVID-19 vaccination on physiological immunological, cardiovascular and psychosomatic health parameters. This data is presented in the current study. We show that isolated PBMCs from individuals vaccinated against COVID-19 show a ~ 600-fold increase in basal and a ~ 6000-fold increase in ConA-induced proinflammatory IL-6 secretion, and a ~ 2-fold increase in basal and ConA-induced antiinflammatory IL-10 secretion, both in comparison with non-vaccinated individuals. In contrast, LPS-induced ex vivo IL-6 and IL-10 secretions were not affected by vaccination status, as were plasma IL-6 concentrations, complete blood counts, salivary cortisol and α-amylase, cardiovascular measures and psychosomatic health. In summary, our findings are of relevance for many clinical studies ran before/during the pandemic, clearly indicating that consideration of participants’ vaccination status is critical, at least when assessing ex vivo PBMC functionality.

Abstract Severe injuries are frequently accompanied by hemorrhagic shock and harbor an increased risk for complications. Local or systemic inflammation after trauma/hemorrhage may lead to a leaky intestinal epithelial barrier and subsequent translocation of gut microbiota, potentially worsening outcomes. To evaluate the extent with which trauma affects the gut microbiota composition, we performed a post hoc analysis of a murine model of polytrauma and hemorrhage. Four hours after injury, organs and plasma samples were collected, and the diversity and composition of the cecal microbiome were evaluated using 16S rRNA gene sequencing. Although cecal microbial alpha diversity and microbial community composition were not found to be different between experimental groups, norepinephrine support in shock animals resulted in increased alpha diversity, as indicated by higher numbers of distinct microbial features. We observed that the concentrations of proinflammatory mediators in plasma and intestinal tissue were associated with measures of microbial alpha and beta diversity and the presence of specific microbial drivers of inflammation, suggesting that the composition of the gut microbiome at the time of trauma, or shortly after trauma exposure, may play an important role in determining physiological outcomes. In conclusion, we found associations between measures of gut microbial alpha and beta diversity and the severity of systemic and local gut inflammation. Furthermore, our data suggest that four hours following injury is too early for development of global changes in the alpha diversity or community composition of the intestinal microbiome. Future investigations with increased temporal-spatial resolution are needed in order to fully elucidate the effects of trauma and shock on the gut microbiome, biological signatures of inflammation, and proximal and distal outcomes.