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Aberrant intestinal inflammation plays a critical role in the development of colitis-associated colorectal cancer (CAC), yet the mechanisms controlling tumor development by the myeloid immune compartment are not fully understood. Although altered microRNA expression is observed in CAC, it is also unclear how myeloid-specific microRNAs impact the inflammatory process that underpins the continuum from ulcerative colitis to tumorigenesis. In this study, we report that miR-223 acts to limit myeloid-driven inflammation in the azoxymethane (AOM)-dextran sodium sulfate (DSS) model of CAC in mice. In this model, miR-223-/y mice present with significantly larger tumors with an enhanced proliferative signature. Immunoprofiling showed that miR-223-/y mice have significantly increased colonic myeloid immune infiltrate (neutrophils, monocytes, and macrophages) following AOM-DSS. This was accompanied by an increased inflammatory chemokine and cytokine signature for monocytes and neutrophils. Bone marrow chimera studies demonstrate that myeloid-expressed miR-223 is responsible for the enhanced tumor proliferation and inflammatory response. RNA sequencing identified several pathways that could be contributing to the development of CAC in miR-223-/y mice, including the IL-6/IL-17a cytokine family and STAT3 signaling. Lastly, neutrophil depletion with an anti-GR1 Ab (Ly6G/Ly6C) during the initial phase of the AOM-DSS model reduced the tumor burden in miR-223-/y mice. Collectively, our data indicate that miR-223 is an important regulator of mucosal inflammation and acts to constrain the progression from ulcerative colitis to CAC by limiting myeloid-associated inflammation., (Copyright © 2024 by The American Association of Immunologists, Inc.)

Anesthesia can influence cerebral blood flow by altering vessel diameter. Using in vivo two-photon imaging, we examined the effects of volatile anesthetics, sevoflurane and isoflurane, on vessel diameter in young and adult mice. Our results show that these anesthetics induce robust dilation of cortical arterioles and arteriole-proximate capillaries in adult mice, with milder effects in juveniles and no dilation in infants. This anesthesia-induced vasodilation correlates with decreased cytosolic Ca 2+ levels in NG2 + vascular mural cells. Optogenetic manipulation of these cells bidirectionally regulates vessel diameter, and their ablation abolishes the vasodilatory response to anesthetics. In immature brains, NG2 + mural cells are fewer in number and express lower levels of Kir6.1, a subunit of ATP-sensitive potassium channels. This likely contributes to the age-dependent differences in vasodilation, as Kir6.1 activation promotes, while its inhibition reduces, anesthesia-induced vasodilation. These findings highlight the essential role of NG2 + mural cells in mediating anesthesia-induced cerebral vasodilation., Competing Interests: Competing interests The authors declare no competing interests., (© 2024. The Author(s).)

Recent efforts to chart human brain growth across the lifespan using large-scale MRI data have provided reference standards for human brain development. However, similar models for nonhuman primate (NHP) growth are lacking. The rhesus macaque, a widely used NHP in translational neuroscience due to its similarities in brain anatomy, phylogenetics, cognitive, and social behaviors to humans, serves as an ideal NHP model. This study aimed to create normative growth charts for brain structure across the macaque lifespan, enhancing our understanding of neurodevelopment and aging, and facilitating cross-species translational research. Leveraging data from the PRIMatE Data Exchange (PRIME-DE) and other sources, we aggregated 1,522 MRI scans from 1,024 rhesus macaques. We mapped non-linear developmental trajectories for global and regional brain structural changes in volume, cortical thickness, and surface area over the lifespan. Our findings provided normative charts with centile scores for macaque brain structures and revealed key developmental milestones from prenatal stages to aging, highlighting both species-specific and comparable brain maturation patterns between macaques and humans. The charts offer a valuable resource for future NHP studies, particularly those with small sample sizes. Furthermore, the interactive open resource (https://interspeciesmap.childmind.org) supports cross-species comparisons to advance translational neuroscience research.

The concern about anesthesia-induced developmental neurotoxicity (AIDN) in infants and young children arises from animal studies indicating potential long-term neurobehavioral impairments following early-in-life anesthesia exposure. While initial clinical studies provided ambiguous results, recent prospective assessments in children indicate associations between early-in-life anesthesia exposure and later behavioral alterations. Ethical constraints and confounding factors in clinical studies pose challenges in establishing a direct causal link and in investigating its mechanisms. This commentary on a recent study in non-human primates (NHPs) focuses on exploring the role of neuroinflammation and alterations in brain functional connectivity in the behavioral impairments following early-in-life anesthesia exposure. In juvenile NHPs, chronic astrogliosis in the amygdala correlates with alterations in functional connectivity between this area with other regions of the brain and with the behavioral impairments, suggesting a potential mechanism for AIDN. Despite acknowledging the study's limitations, these findings emphasize the need for further research with larger cohorts to confirm these associations and to establish a causal link between the neuroinflammation and the behavioral alterations associated with early-in-life anesthesia exposure., Competing Interests: Declaration of Conflicting Interests The authors declare that there is no conflict of interest.

Background: Clinical studies suggest that anaesthesia exposure early in life affects neurobehavioural development. We designed a non-human primate (NHP) study to evaluate cognitive, behavioural, and brain functional and structural alterations after isoflurane exposure during infancy. These NHPs displayed decreased close social behaviour and increased astrogliosis in specific brain regions, most notably in the amygdala. Here we hypothesise that resting-state functional connectivity MRI can detect alterations in connectivity of brain areas that relate to these social behaviours and astrogliosis., Methods: Imaging was performed in 2-yr-old NHPs under light anaesthesia, after early-in-life (postnatal days 6-12) exposure to 5 h of isoflurane either one or three times, or to room air. Brain images were segmented into 82 regions of interest; the amygdala and the posterior cingulate cortex were chosen for a seed-based resting-state functional connectivity MRI analysis., Results: We found differences between groups in resting-state functional connectivity of the amygdala and the auditory cortices, medial premotor cortex, and posterior cingulate cortex. There were also alterations in resting-state functional connectivity between the posterior cingulate cortex and secondary auditory, polar prefrontal, and temporal cortices, and the anterior insula. Relationships were identified between resting-state functional connectivity alterations and the decrease in close social behaviour and increased astrogliosis., Conclusions: Early-in-life anaesthesia exposure in NHPs is associated with resting-state functional connectivity alterations of the amygdala and the posterior cingulate cortex with other brain regions, evident at the juvenile age of 2 yr. These changes in resting-state functional connectivity correlate with the decrease in close social behaviour and increased astrogliosis. Using resting-state functional connectivity MRI to study the neuronal underpinnings of early-in-life anaesthesia-induced behavioural alterations could facilitate development of a biomarker for anaesthesia-induced developmental neurotoxicity., (Copyright © 2023 British Journal of Anaesthesia. Published by Elsevier Ltd. All rights reserved.)

Competing Interests: The authors have no conflicts of interest to disclose.

Background: Infant anaesthesia causes acute brain cell apoptosis, and later in life cognitive deficits and behavioural alterations, in non-human primates (NHPs). Various brain injuries and neurodegenerative conditions are characterised by chronic astrocyte activation (astrogliosis). Glial fibrillary acidic protein (GFAP), an astrocyte-specific protein, increases during astrogliosis and remains elevated after an injury. Whether infant anaesthesia is associated with a sustained increase in GFAP is unknown. We hypothesised that GFAP is increased in specific brain areas of NHPs 2 yr after infant anaesthesia, consistent with prior injury., Methods: Eight 6-day-old NHPs per group were exposed to 5 h isoflurane once (1×) or three times (3×), or to room air as a control (Ctr). Two years after exposure, their brains were assessed for GFAP density changes in the primary visual cortex (V1), perirhinal cortex (PRC), hippocampal subiculum, amygdala, and orbitofrontal cortex (OFC). We also assessed concomitant microglia activation and hippocampal neurogenesis., Results: Compared with controls, GFAP densities in V1 were increased in exposed groups (Ctr: 0.208 [0.085-0.427], 1×: 0.313 [0.108-0.533], 3×: 0.389 [0.262-0.652]), whereas the density of activated microglia was unchanged. In addition, GFAP densities were increased in the 3× group in the PRC and the subiculum, and in both exposure groups in the amygdala, but there was no increase in the OFC. There were no differences in hippocampal neurogenesis among groups., Conclusions: Two years after infant anaesthesia, NHPs show increased GFAP without concomitant microglia activation in specific brain areas. These long-lasting structural changes in the brain caused by infant anaesthesia exposure may be associated with functional alterations at this age., (Copyright © 2021 British Journal of Anaesthesia. Published by Elsevier Ltd. All rights reserved.)

Purpose of Review: Long-term behavioural and cognitive impairments after exposure to general anaesthetics during infancy is an intensely investigated and controversial topic. Recent clinical studies with prospective assessments associate exposure with long-term behavioural alterations rather than cognitive impairments. This review aims to provide an understanding of the long-term cognitive impairments and behavioural alterations found in recent animal studies and to summarize latest advances in strategies to protect against anaesthesia-induced developmental neurotoxicity (AIDN)., Recent Findings: Preclinical studies, particularly those in nonhuman primates (NHPs), provide accumulating evidence that anaesthesia exposure during infancy is associated with long-term alterations in behaviour, but cognitive impairments are more controversial. Results from recent studies aiming to find mitigating strategies to reduce AIDN or to identify alternative anaesthetic agents include the co-administration of dexmedetomidine with the anaesthetic drugs or the alternative use of hypnotic neurosteroids without being harmful to the developing brain., Summary: Recent findings in animal studies with translational relevance support the proposed association between early-in-life anaesthesia exposure and long-term alterations in behaviour. Studies aiming to prevent AIDN are promising and need evaluation in the NHP model. The careful design of subsequent translational studies will be critical to advance the field forward towards safer anaesthesia exposure in children., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Clinical studies show that children exposed to anaesthetics for short times at young age perform normally on intelligence tests, but display altered social behaviours. In non-human primates (NHPs), infant anaesthesia exposure for several hours causes neurobehavioural impairments, including delayed motor reflex development and increased anxiety-related behaviours assessed by provoked response testing. However, the effects of anaesthesia on spontaneous social behaviours in juvenile NHPs have not been investigated. We hypothesised that multiple, but not single, 5 h isoflurane exposures in infant NHPs are associated with impairments in specific cognitive domains and altered social behaviours at juvenile age., Methods: Eight Rhesus macaques per group were anaesthetised for 5 h using isoflurane one (1×) or three (3×) times between postnatal days 6 and 12 or were exposed to room air (control). Cognitive testing, behavioural assessments in the home environment, and provoked response testing were performed during the first 2 yr of life., Results: The cognitive functions tested did not differ amongst groups. However, compared to controls, NHPs in the 3× group showed less close social behaviour (P=0.016), and NHPs in the 1× group displayed increased anxiety-related behaviours (P=0.038) and were more inhibited towards novel objects (P<0.001)., Conclusions: 5 h exposures of NHPs to isoflurane during infancy are associated with decreased close social behaviour after multiple exposures and more anxiety-related behaviours and increased behavioural inhibition after single exposure, but they do not affect the cognitive domains tested. Our findings are consistent with behavioural alterations in social settings reported in clinical studies, which may guide future research., Competing Interests: Declarations of interest The authors declare that they have no conflicts of interest., (Copyright © 2020 British Journal of Anaesthesia. Published by Elsevier Ltd. All rights reserved.)

Background: Preclinical studies suggest that exposures of infant animals to general anesthetics cause acute neurotoxicity and affect their neurobehavioral development representing a potential risk to human infants undergoing anesthesia. Alternative or mitigating strategies to counteract such adverse effects are desirable. Dexmedetomidine (DEX) is a clinically established sedative with potential neuroprotective properties. DEX ameliorates experimental brain injury as well as neurotoxicity caused by anesthetic doses of sevoflurane (SEVO) or other general anesthetics in infant animals. However, it is unknown whether DEX also is beneficial when given together with lower doses of these drugs. Here we tested the hypothesis that DEX co-administration with a sub-anesthetic dose of SEVO reduces responsiveness to external stimuli while also protecting against SEVO-induced brain cell apoptosis., Method: Rats were exposed on postnatal day 7 for 6 h to SEVO 1.1, 1.8, or 2.5% and were given intraperitoneal injections of saline or DEX at different doses (1-25 μg/kg) three times during the exposure. Responsiveness to external stimuli, respiratory rates, and blood gases were assessed. Apoptosis was determined in cortical and subcortical brain areas by activated caspase-3 immunohistochemistry., Results: Rats exposed to SEVO 1.1% alone were sedated but still responsive to external stimuli whereas those exposed to SEVO 1.8% reached complete unresponsiveness. SEVO-induced brain cell apoptosis increased dose-dependently, with SEVO 1.1% causing a small increase in apoptosis above that in controls. Co-administration of DEX at 1 μg/kg did not alter the responsiveness to stimuli nor the apoptosis induced by SEVO 1.1%. In contrast, co-administration of DEX at 5 μg/kg or higher with SEVO 1.1% reduced responsiveness but potentiated apoptosis., Conclusions: In the neonatal rat model, co-administration of a clinically relevant dose of DEX (1 μg/kg) with a sub-anesthetic dose of SEVO (1.1%) does not affect the neurotoxicity of the anesthetic while co-administration of higher doses of DEX with SEVO 1.1% potentiates it., Competing Interests: Declaration of Competing Interest The authors report no declarations of interest., (Copyright © 2020 Elsevier B.V. All rights reserved.)

MicroRNAs were discovered more than 2 decades ago and have profound impact on diverse biological processes. Specific microRNAs have important roles in modulating the innate immune response and their dysregulation has been demonstrated to contribute to inflammatory diseases. MiR-223 in particular, is very highly expressed and tightly regulated in hematopoietic cells. It functions as key modulator for the differentiation and activation of myeloid cells. The central role of miR-223 in myeloid cells, especially neutrophil and macrophage differentiation and activation has been studied extensively. MiR-223 contributes to myeloid differentiation by enhancing granulopoiesis while inhibiting macrophage differentiation. Uncontrolled myeloid activation has detrimental consequences in inflammatory disease. MiR-223 serves as a negative feedback mechanism controlling excessive innate immune responses in the maintenance of myeloid cell homeostasis. This review summarizes several topics covering the function of miR-223 in myeloid differentiation, neutrophil and macrophage functions, as well as in inflammatory diseases including acute respiratory distress syndrome and inflammatory bowel disease. In addition, nonmyeloid functions of miR-223 are also discussed in this review. Therapeutic enhancement of miR-223 to dampen inflammatory targets is also highlighted as potential treatment to control excessive innate immune responses during mucosal inflammation., (©2018 Society for Leukocyte Biology.)

Perioperative organ injury has a significant impact on surgical outcomes and presents a leading cause of death in the United States. Recent research has pointed out an important role of hypoxia signaling in the protection from organ injury, including for example myocardial infarction, acute respiratory distress syndrome, acute kidney, or gut injury. Hypoxia induces the stabilization of hypoxia-inducible factors (HIFs), thereby leading to the induction of HIF target genes, which facilitates adaptive responses to low oxygen. In this review, we focus on current therapeutic strategies targeting hypoxia signaling in various organ injury models and emphasize potential clinical approaches to integrate these findings into the care of surgical patients. Conceptually, there are 2 options to target the HIF pathway for organ protection. First, drugs became recently available that promote the stabilization of HIFs, most prominently via inhibition of prolyl hydroxylase. These compounds are currently trialed in patients, for example, for anemia treatment or prevention of ischemia and reperfusion injury. Second, HIF target genes (such as adenosine receptors) could be activated directly. We hope that some of these approaches may lead to novel pharmacologic strategies to prevent or treat organ injury in surgical patients.

Intercellular transfer of microRNAs can mediate communication between critical effector cells. We hypothesized that transfer of neutrophil-derived microRNAs to pulmonary epithelial cells could alter mucosal gene expression during acute lung injury. Pulmonary-epithelial microRNA profiling during coculture of alveolar epithelial cells with polymorphonuclear neutrophils (PMNs) revealed a selective increase in lung epithelial cell expression of microRNA-223 ( miR-223 ). Analysis of PMN-derived supernatants showed activation-dependent release of miR-223 and subsequent transfer to alveolar epithelial cells during coculture in vitro or after ventilator-induced acute lung injury in mice. Genetic studies indicated that miR-223 deficiency was associated with severe lung inflammation, whereas pulmonary overexpression of miR-223 in mice resulted in protection during acute lung injury induced by mechanical ventilation or by infection with Staphylococcus aureus Studies of putative miR-223 gene targets implicated repression of poly(adenosine diphosphate-ribose) polymerase-1 (PARP-1) in the miR-223 -dependent attenuation of lung inflammation. Together, these findings suggest that intercellular transfer of miR-223 from neutrophils to pulmonary epithelial cells may dampen acute lung injury through repression of PARP-1., (Copyright © 2017 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.)

Of the total human body's surface, the majority is internal surface, belonging to the lungs (100 m 2 ) and intestinal tract (400 m 2 ). In comparison, the external surface area, belonging to the skin, comprises less than 1% (2 m 2 ). Continuous exposure of the mucosal surface to external factors (e.g., pathogens, food particles) requires tight regulation to maintain homeostasis. MicroRNAs (miRNAs) have gained noticeable attention as playing important roles in maintaining the steady-state of tissues by modulating immune functions and inflammatory responses. Accordingly, associations have been found between miRNA expression levels and human health conditions and diseases. These findings have important implications in inflammatory diseases involving pulmonary and intestinal mucosa, such as acute lung injury or inflammatory bowel disease. In this review, we highlight the known biology of miRNAs and discuss the role of miRNAs in modulating mucosal defense and homeostasis. Additionally, we discuss miRNAs serving as potential therapeutic targets to treat immunological conditions, particularly mucosal inflammation.

Sepsis outcomes are heavily dependent on the development of septic organ injury, but no interventions exist to interrupt or reverse this process. microRNA-223 (miR-223) is known to be involved in both inflammatory gene regulation and host-pathogen interactions key to the pathogenesis of sepsis. The goal of this study was to determine the role of miR-223 as a mediator of septic kidney injury. Using miR-223 knockout mice and multiple models of experimental sepsis, we found that miR-223 differentially influences acute kidney injury (AKI) based on the model used. In the absence of miR-223, mice demonstrated exaggerated AKI in sterile models of sepsis (LPS injection) and attenuated AKI in a live-infection model of sepsis (cecal ligation and puncture). We demonstrated that miR-223 expression is induced in kidney homogenate after cecal ligation and puncture, but not after LPS or fecal slurry injection. We investigated additional potential mechanistic explanations including differences in peritoneal bacterial clearance and host stool virulence. Our findings highlight the complex role of miR-223 in the pathogenesis of septic kidney injury, as well as the importance of differences in experimental sepsis models and their consequent translational applicability., (Copyright © 2017 the American Physiological Society.)

MicroRNA (miRNA)-mediated RNA interference regulates many immune processes, but how miRNA circuits orchestrate aberrant intestinal inflammation during inflammatory bowel disease (IBD) is poorly defined. Here, we report that miR-223 limits intestinal inflammation by constraining the nlrp3 inflammasome. miR-223 was increased in intestinal biopsies from patients with active IBD and in preclinical models of intestinal inflammation. miR-223 -/y mice presented with exacerbated myeloid-driven experimental colitis with heightened clinical, histopathological, and cytokine readouts. Mechanistically, enhanced NLRP3 inflammasome expression with elevated IL-1β was a predominant feature during the initiation of colitis with miR-223 deficiency. Depletion of CCR2 + inflammatory monocytes and pharmacologic blockade of IL-1β or NLRP3 abrogated this phenotype. Generation of a novel mouse line, with deletion of the miR-223 binding site in the NLRP3 3' untranslated region, phenocopied the characteristics of miR-223 -/y mice. Finally, nanoparticle-mediated overexpression of miR-223 attenuated experimental colitis, NLRP3 levels, and IL-1β release. Collectively, our data reveal a previously unappreciated role for miR-223 in regulating the innate immune response during intestinal inflammation., (© 2017 Neudecker et al.)

MicroRNAs (miRNAs) are small, non-protein-coding, single-stranded RNAs. They function as posttranscriptional regulators of gene expression by interacting with target mRNAs. This process prevents translation of target mRNAs into a functional protein. miRNAs are considered to be functionally involved in virtually all physiologic processes, including differentiation and proliferation, metabolism, hemostasis, apoptosis, and inflammation. Many of these functions have important implications for anesthesiology and critical care medicine. Studies indicate that miRNA expression levels can be used to predict the risk for eminent organ injury or sepsis. Pharmacologic approaches targeting miRNAs for the treatment of human diseases are currently being tested in clinical trials. The present review highlights the important biological functions of miRNAs and their usefulness as perioperative biomarkers and discusses the pharmacologic approaches that modulate miRNA functions for disease treatment. In addition, the authors discuss the pharmacologic interactions of miRNAs with currently used anesthetics and their potential to impact anesthetic toxicity and side effects.