CXCL1/CXCR2 is involved in white matter injury in neonatal rats via the gut–brain axis

Yang, Can; Feng, Zhiyuan; Deng, Hansheng; Dai, Lu; He, Ling; Yin, Linlin; Zhao, Jing

doi:10.1186/s12868-022-00749-1

Cited by 6 publications

(7 citation statements)

References 37 publications

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“…We did not find a difference in NeuN-positive mature neurons in mice with enterocolitis versus controls (Figure 5). Our microglia and neuron results contrast with other groups, which found that NEC induction decreased mature neurons and increased microglia numbers in the hippocampus, basal ganglia, and cerebral cortex of pigs and mice [13,34,47]. However, these studies used different ages, induction protocols, and employed different animal species, where cell development and number may innately differ.…”

Section: Implications For the Gut-brain Axiscontrasting

confidence: 99%

“…Consistent with other groups [15, 34], DSS exposure in neonatal mice results in enterocolitis and, to a lesser extent, colitis (Figure 2A-C), which contrasts with DSS’s effects in adult mice [27]. Increased DSS supplementation resulted in worse macroscopic gut assessment scores (bowel distension, bloody stool, and friability), which correlates with NEC severity in other models [18].…”

Section: Discussionsupporting

confidence: 87%

“…In our experiments, formula-fed mice also had a significant mortality rate, which highlights the difficulty of gavage feeding of neonatal mice (2 grams) who are also stressed by separation from their dams [17]. Consistent with other groups [15,34], DSS exposure in neonatal mice results in enterocolitis and, to a lesser extent, colitis (Figure 2A-C), which contrasts with DSS's effects in adult mice [27]. Increased DSS supplementation resulted in worse macroscopic gut assessment scores (bowel distension, bloody stool, and friability), which correlates with NEC severity in other models [18].…”

Section: A Graded Mouse Model Of Necsupporting

confidence: 85%

“…DSS administration to adult mice primarily leads to colitis [27], whereas in neonatal mice and rats, it causes small and large bowel inflammation [15, 34]. We supplemented enteral feeds with different concentrations of DSS – 0.25%, 1%, 2% and 3% DSS – to create a graded model of NEC.…”

Section: Discussionmentioning

confidence: 99%

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A graded neonatal mouse model of necrotizing enterocolitis demonstrates that mild enterocolitis is sufficient to activate microglia and increase cerebral cytokine expression

Sha,

Van Brunt,

Kudria

et al. 2023

Preprint

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Necrotizing enterocolitis (NEC) is an inflammatory gastrointestinal process that afflicts nearly 10% of premature babies born in the United States each year, with a mortality rate of 15-30%. NEC severity is graded using the Bells classification system based on the presenting symptoms and radiological findings. Animal models are a valuable tool in studying the pathogenesis of this disease; however, prior models cannot control the severity of NEC induced, a critical aspect of the disease in human infants. Here, we aim to bridge this gap in knowledge through development of a murine model of NEC with graded characteristics. Postnatal day 3 (P3) C57BL/6 mice were fed formula containing different concentrations (0.25%, 1%, 2%, and 3%) of dextran sodium sulfate (DSS), an osmotic agent previously shown to induce severe NEC in neonatal mice. P3 mice were fed every 3 hours over a 72-hour period. During feeding, we collected data on weight gain and behavior, which included activity, response, and body color. After feeding, at P6, we dissected the mice to check for bowel features and collect organs for immunohistochemistry and cytokine analysis. Mice fed formula only or 0% DSS were used as a control instead of breastfed mice. Since staying with the dam during the first week of life is vital to normal development in mice, using formula-fed mice as the control accounts for the handling bias that exists during feeding. Comparing breastfed and formula-fed mice alone, weight gain was significantly greater in breastfed mice, and liver cytokine concentrations tended to be higher. In the established graded NEC model, clinical differences were seen among the mice fed different DSS concentrations. Over the course of NEC induction, mice fed higher concentrations of DSS lost weight quicker and exhibited greater clinical severity scores. External bowel scores (dilation, color, and friability) were considerably worse in mice fed higher DSS concentrations; although internal small bowel pathology showed intestinal disarray among mice fed all DSS concentrations. Staining for cellular proliferation marker Ki-67 in intestines shows that mice fed higher concentrations of DSS display less cell proliferation at the base of the small intestine crypts. Pro-inflammatory cytokine levels in the liver, to assess systemic inflammation downstream of the gastrointestinal system, trended higher in mice fed with higher concentrations of DSS. Here, we demonstrate that we have successfully characterized a graded newborn mouse model where NEC severity can be predictably induced. This mouse model will be a valuable tool in gaining greater insight and understanding of the pathophysiology of this devastating disease process and to understand its long-term complications, such as neurodevelopmental impairment.

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Section: Implications For the Gut-brain Axiscontrasting

confidence: 99%

Section: Discussionsupporting

confidence: 87%

Section: A Graded Mouse Model Of Necsupporting

confidence: 85%

Section: Discussionmentioning

confidence: 99%

See 2 more Smart Citations

A graded neonatal mouse model of necrotizing enterocolitis demonstrates that mild enterocolitis is sufficient to activate microglia and increase cerebral cytokine expression

Sha,

Van Brunt,

Kudria

et al. 2023

Preprint

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“…Another level of complexity arises from crosstalk between the brain and other organs. Several studies have reported on reciprocal interactions between the injured or diseased brain with the gut microbiome and how therapeutic drugs may influence these interactions [ 17 – 20 ]. Moreover, organ dysfunction has been recognized to be bidirectional, meaning that dysfunction in one organ potentiates injury to others.…”

mentioning

confidence: 99%

Neuroinflammation and Brain Disease

2023

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Starting from the perspective of an immune-privileged site, our knowledge of the inflammatory processes within the central nervous system has increased rapidly over the last 30 years, leading to a rather puzzling picture today. Of particular interest is the emergence of disease- and injury-specific inflammatory responses within the brain, which may form the basis for future therapeutic approaches. To advance this important topic, we invite authors to contribute research and clinical papers to the Collection “Neuroinflammation and Brain Disease”.

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CXCR2 immunomodulatory therapy protects against microstructural white matter injury and gait abnormalities but does not mitigate deficits of cognition in a preclinical model of cerebral palsy

Kitase,

Madurai,

Boyd

et al. 2024

Journal of Neurochemistry

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Minimizing central nervous system (CNS) injury from preterm birth depends upon understanding the critical pathways that underlie essential neurodevelopmental and CNS pathophysiology. Signaling by chemokine (C‐X‐C motif) ligand 1 (CXCL1) through its cognate receptor, CXCR2 [(C‐X‐C motif) receptor 2] is essential for neurodevelopment. Increased CXCR2 signaling, however, is implicated in a variety of uterine and neuropathologies, and their role in the CNS injury associated with perinatal brain injury is poorly defined. To evaluate the long‐term efficacy of CXCR2 blockade in functional repair of brain injury secondary to chorioamnionitis (CHORIO), we used an established preclinical rat model of cerebral palsy. We tested the hypothesis that transient postnatal CXCR2 antagonism with SB225002 would reduce gait deficits, hypermobility, hyperactivity, and disinhibition concomitant with repair of functional and anatomical white and gray matter injury. CHORIO was induced in pregnant Sprague Dawley rats on embryonic day 18 (E18). SB225002 (3 mg/kg) was administered intraperitoneally from postnatal day 1 (P1)‐P5. Rats were aged to adulthood and tested for gait, open‐field behavior and cognitive and executive function deficits using a touchscreen cognitive assessment platform. Results show that transient CXCR2 blockade attenuated microstructural white matter injury after CHORIO consistent with improved anatomical connectivity, and mitigated deficits in gait coordination, posture, balance, paw placement, and stepping (p < 0.05). Animals with CHORIO were hyperactive and hypermobile with fMRI deficits in neural circuitry central to cognition. However, CXCR2 antagonism in CHORIO animals did not normalize open‐field behavior, neural activity, or cognition on a touchscreen task of discrimination learning (all p > 0.05). Studies in CXCR2 knockout mice confirmed significantly impaired cognitive performance independent of CHORIO. Taken together, transient postnatal blockade of CXCR2 ameliorates aspects of the lasting neural injury after CHORIO including normalizing gait deficits and white matter injury. However, improvement in essential functional and cognitive domains are not achieved limiting the utility of this therapeutic approach for treatment of perinatal brain injury. This study emphasizes the complex, multi‐faceted role of chemokines in typical neurodevelopment, circuit formation, neural network function, and injury response.image

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CXCL1/CXCR2 is involved in white matter injury in neonatal rats via the gut–brain axis

Cited by 6 publications

References 37 publications

A graded neonatal mouse model of necrotizing enterocolitis demonstrates that mild enterocolitis is sufficient to activate microglia and increase cerebral cytokine expression

A graded neonatal mouse model of necrotizing enterocolitis demonstrates that mild enterocolitis is sufficient to activate microglia and increase cerebral cytokine expression

Neuroinflammation and Brain Disease

CXCR2 immunomodulatory therapy protects against microstructural white matter injury and gait abnormalities but does not mitigate deficits of cognition in a preclinical model of cerebral palsy

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