Reduced ambient temperature exacerbates SIRS-induced cardiac autonomic dysregulation and myocardial dysfunction in mice

Ndongson-Dongmo, Bernadin; Lang, G.; Meçe, Odeta; Hechaichi, Nadine; Lajqi, Trim; Hoyer, Dirk; Brodhun, Michael; Heller, Regine; Wetzker, Reinhard; Franz, Marcus; Levy, Finn Olav; Bauer, Reinhard

doi:10.1007/s00395-019-0734-1

Cited by 19 publications

(14 citation statements)

References 107 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The recent findings in mice showed that a reduced ambient temperature exacerbates SIRS-induced cardiac autonomic dysregulation and myocardial dysfunction [45]. This study in the heart supports the present results and conclusions on the brain response to cold stress.…”

Section: Discussionsupporting

confidence: 92%

Impact of Ambient Temperature on Inflammation-induced Encephalopathy in Endotoxemic Mice—Role of Phosphoinositide 3-Kinase Gamma

Lang

Ndongson-Dongmo

Lajqi

et al. 2020

Preprint

Self Cite

View full text Add to dashboard Cite

Background: Sepsis-associated encephalopathy (SAE) is an early and frequent event of infection-induced systemic inflammatory response syndrome. Phosphoinositide 3-kinase γ (PI3Kγ) is linked to neuroinflammation and inflammation-related microglial activity. In homeotherms, variations in ambient temperature (Ta) outside the thermoneutral zone lead to thermoregulatory responses, mainly driven by a gradually increasing sympathetic activity, and may affect disease severity. We hypothesized that thermoregulatory response to hypothermia (reduced Ta) aggravates SAE in PI3Kγ-dependent manner.Methods: Experiments were performed in wild-type, PI3Kγ knockout, and PI3Kγ kinase-dead mice, which were kept at neutral (30±0.5°C) or moderately lowered (26±0.5°C) Ta. Mice were exposed to lipopolysaccharide (LPS, 10 μg/g, from Escherichia coli serotype 055:B5, single intraperitoneal injection) - evoked systemic inflammatory response (SIR) and monitored 24 hours for thermoregulatory response and blood–brain barrier integrity. Primary microglial cells and brain tissue derived from treated mice were analyzed for inflammatory responses and related cell functions. Comparisons between groups were made with one-way or two-way analysis of variance, as appropriate. Post hoc comparisons were made with the Holm–Sidak test or t-tests with Bonferroni’s correction for adjustments of multiple comparisons. Data not following normal distribution was tested with Kruskal-Wallis test followed by Dunn’s multiple comparisons test.Results: We show that a moderate reduction of ambient temperature triggers enhanced hypothermia of mice undergoing LPS-induced systemic inflammation by aggravated SAE. PI3Kγ deficiency enhances blood–brain barrier injury and upregulation of matrix metalloproteinases (MMPs) as well as an impaired microglial phagocytic activity.Conclusions: Thermoregulatory adaptation in response to ambient temperatures below the thermoneutral range exacerbates LPS-induced blood–brain barrier injury and neuroinflammation. PI3Kγ serves a protective role in suppressing release of MMPs, maintaining microglial motility and reinforcing phagocytosis leading to improved brain tissue integrity. Thus, preclinical research targeting severe brain inflammation responses is seriously biased when basic physiological prerequisites of mammal species such as preferred ambient temperature are ignored.

show abstract

Section: Discussionsupporting

confidence: 92%

Impact of Ambient Temperature on Inflammation-induced Encephalopathy in Endotoxemic Mice—Role of Phosphoinositide 3-Kinase Gamma

Lang

Ndongson-Dongmo

Lajqi

et al. 2020

Preprint

Self Cite

View full text Add to dashboard Cite

show abstract

“…1-2 A-F, available at https://doi.org/10.1523/JNEUROSCI.2324-19.2020.f1-2), indicating that neuronal Mfn2-regulated cardiac function, potentially through autonomic regulation, is likely an important mechanism for the suppression of lethality associated with septic shock in TMFN mice. In support of this notion, previous studies have identified autonomic control of myocardial dysfunction in LPS rodent models, particularly through cholinergic neurons of the sympathovagal system (Plaschke et al, 2018;Sallam et al, 2018;Ndongson-Dongmo et al, 2019). Nevertheless, additional work is still needed to clarify whether autonomic neurotransmission is altered by Mfn2 overexpression in neurons.…”

Section: Discussionmentioning

confidence: 87%

Neuronal Mitochondria Modulation of LPS-Induced Neuroinflammation

Harland¹,

Torres²,

Liu³

et al. 2020

J. Neurosci.

View full text Add to dashboard Cite

Neuronal mitochondria dysfunction and neuroinflammation are two prominent pathological features increasingly realized as important pathogenic mechanisms for neurodegenerative diseases. However, little attempt has been taken to investigate the likely interactions between them. Mitofusin2 (Mfn2) is a mitochondrial outer membrane protein regulating mitochondrial fusion, a dynamic process essential for mitochondrial function. To explore the significance of neuronal mitochondria in the regulation of neuroinflammation, male and female transgenic mice with forced overexpression of Mfn2 specifically in neurons were intraperitoneally injected with lipopolysaccharide (LPS), a widely used approach to model neurodegeneration-associated neuroinflammation. Remarkably, LPS-induced lethality was almost completely abrogated in neuronal Mfn2 overexpression mice. Compared with nontransgenic wild-type mice, mice with neuronal Mfn2 overexpression also exhibited alleviated bodyweight loss, behavioral sickness, and myocardial dysfunction. LPS-induced release of IL-1␤ but not TNF-␣ was further found greatly inhibited in the CNS of mice with neuronal Mfn2 overexpression, whereas peripheral inflammatory responses in the blood, heart, lung, and spleen remained unchanged. At the cellular and molecular levels, neuronal Mfn2 suppressed the activation of microglia, prevented LPS-induced mitochondrial fragmentation in neurons, and importantly, upregulated the expression of CX3CL1, a unique chemokine constitutively produced by neurons to suppress microglial activation. Together, these results reveal an unrecognized possible role of neuronal mitochondria in the regulation of microglial activation, and propose neuronal Mfn2 as a likely mechanistic linker between neuronal mitochondria dysfunction and neuroinflammation in neurodegeneration.

show abstract

“…In contrast, when housed at thermoneutrality, Ucp1 knockout mice have increased sensitivity to diet-induced obesity (42,43). The fundamental difference in thermoregulation between mice and humans and the growing number of examples that housing temperature influences experimental outcomes (3,(44)(45)(46)(47)(48)(49)(50)(51)(52)(53)(54)(55)(56)(57)(58)(59) argue strongly that thermoneutral housing of mice more accurately reflects the thermal environment in humans and preclinical studies performed in mice should be conducted at housing temperatures that minimize cold stress.…”

Section: Discussionmentioning

confidence: 99%

Effects of Propranolol on Bone, White Adipose Tissue, and Bone Marrow Adipose Tissue in Mice Housed at Room Temperature or Thermoneutral Temperature

et al. 2020

View full text Add to dashboard Cite

Growing female mice housed at room temperature (22 • C) weigh the same but differ in body composition compared to mice housed at thermoneutrality (32 • C). Specifically, mice housed at room temperature have lower levels of white adipose tissue (WAT). Additionally, bone marrow adipose tissue (bMAT) and cancellous bone volume fraction in distal femur metaphysis are lower in room temperature-housed mice. The metabolic changes induced by sub-thermoneutral housing are associated with lower leptin levels in serum and higher levels of Ucp1 gene expression in brown adipose tissue. Although the precise mechanisms mediating adaptation to sub-thermoneutral temperature stress remain to be elucidated, there is evidence that increased sympathetic nervous system activity acting via β-adrenergic receptors plays an important role. We therefore evaluated the effect of the non-specific β-blocker propranolol (primarily β 1 and β 2 antagonist) on body composition, femur microarchitecture, and bMAT in growing female C57BL/6 mice housed at either room temperature or thermoneutral temperature. As anticipated, cancellous bone volume fraction, WAT and bMAT were lower in mice housed at room temperature. Propranolol had small but significant effects on bone microarchitecture (increased trabecular number and decreased trabecular spacing), but did not attenuate premature bone loss induced by room temperature housing. In contrast, propranolol treatment prevented housing temperature-associated differences in WAT and bMAT. To gain additional insight, we evaluated a panel of genes in tibia, using an adipogenesis PCR array. Housing temperature and treatment with propranolol had exclusive as well as shared effects on gene expression. Of particular interest was the finding that room temperature housing reduced, whereas propranolol increased, expression of the gene for acetyl-CoA carboxylase (Acacb), the rate-limiting step for fatty acid synthesis and a key regulator of β-oxidation. Taken together, these findings provide evidence that increased activation of β 1 and/or β 2 receptors contributes to reduced bMAT by regulating adipocyte metabolism, but that this pathway is unlikely to be responsible for premature cancellous bone loss in room temperature-housed mice.

show abstract

Reduced ambient temperature exacerbates SIRS-induced cardiac autonomic dysregulation and myocardial dysfunction in mice

Cited by 19 publications

References 107 publications

Impact of Ambient Temperature on Inflammation-induced Encephalopathy in Endotoxemic Mice—Role of Phosphoinositide 3-Kinase Gamma

Impact of Ambient Temperature on Inflammation-induced Encephalopathy in Endotoxemic Mice—Role of Phosphoinositide 3-Kinase Gamma

Neuronal Mitochondria Modulation of LPS-Induced Neuroinflammation

Effects of Propranolol on Bone, White Adipose Tissue, and Bone Marrow Adipose Tissue in Mice Housed at Room Temperature or Thermoneutral Temperature

Contact Info

Product

Resources

About