Signaling the brain in systemic inflammation: role of sensory circumventricular organs

Alterations in Triggering Receptors Expressed on Myeloid cells (TREM-1/2) are bound to a variety of infectious, sterile inflammatory, and degenerative conditions, ranging from inflammatory bowel disease (IBD) to neurodegenerative disorders. TREMs are emerging as key players in pivotal mechanisms often concurring in IBD and neurodegeneration, namely microbiota dysbiosis, leaky gut, and inflammation. In conditions of dysbiosis, compounds released by intestinal bacteria activate TREMs on macrophages, leading to an exuberant pro-inflammatory reaction up to damage in the gut barrier. In turn, TREM-positive activated macrophages along with inflammatory mediators may reach the brain through the blood, glymphatic system, circumventricular organs, or the vagus nerve via the microbiota-gut-brain axis. This leads to a systemic inflammatory response which, in turn, impairs the blood-brain barrier, while promoting further TREM-dependent neuroinflammation and, ultimately, neural injury. Nonetheless, controversial results still exist on the role of TREM-2 compared with TREM-1, depending on disease specificity, stage, and degree of inflammation. Therefore, the present review aimed to provide an update on the role of TREMs in the pathophysiology of IBD and neurodegeneration. The evidence here discussed the highlights of the potential role of TREMs, especially TREM-1, in bridging inflammatory processes in intestinal and neurodegenerative disorders.

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Elucidating the role of leptin in systemic inflammation: a study targeting physiological leptin levels in rats and their macrophages

AJP Regulatory Integrative and Comparative Physiology ◽

10.1152/ajpregu.00171.2017 ◽

2017 ◽

Vol 313 (5) ◽

pp. R572-R582 ◽

Cited By ~ 9

Author(s):

Elizabeth A. Flatow ◽

Evilin N. Komegae ◽

Monique T. Fonseca ◽

Camila F. Brito ◽

Florin M. Musteata ◽

...

Keyword(s):

Food Deprivation ◽

Systemic Inflammation ◽

Peritoneal Macrophages ◽

Tnf Α ◽

Macrophage Subpopulations ◽

Limited Food ◽

The Brain

To elucidate the role of leptin in acute systemic inflammation, we investigated how its infusion at low, physiologically relevant doses affects the responses to bacterial lipopolysaccharide (LPS) in rats subjected to 24 h of food deprivation. Leptin was infused subcutaneously (0–20 μg·kg−1·h−1) or intracerebroventricularly (0–1 μg·kg−1·h−1). Using hypothermia and hypotension as biomarkers of systemic inflammation, we identified the phase extending from 90 to 240 min post-LPS as the most susceptible to modulation by leptin. In this phase, leptin suppressed the rise in plasma TNF-α and accelerated the recoveries from hypothermia and hypotension. Suppression of TNF-α was not accompanied by changes in other cytokines or prostaglandins. Leptin suppressed TNF-α when infused peripherally but not when infused into the brain. Importantly, the leptin dose that suppressed TNF-α corresponded to the lowest dose that limited food consumption; this dose elevated plasma leptin within the physiological range (to 5.9 ng/ml). We then conducted in vitro experiments to investigate whether an action of leptin on macrophages could parallel our in vivo observations. The results revealed that, when sensitized by food deprivation, LPS-stimulated peritoneal macrophages can be inhibited by leptin at concentrations that are lower than those reported to promote cytokine release. It is concluded that physiological levels of leptin do not exert a proinflammatory effect but rather an anti-inflammatory effect involving selective suppression of TNF-α via an action outside the brain. The mechanism of this effect might involve a previously unrecognized, suppressive action of leptin on macrophage subpopulations sensitized by food deprivation, but future studies are warranted.

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Circumventricular Organs: Gateways to the Brain Role Of Circumventricular Organs (CVO) In Neuroendocrine Responses: Interactions Of Cvo And The Magnocellular Neuroendocrine System In Different Reproductive States

Clinical and Experimental Pharmacology and Physiology ◽

10.1046/j.1440-1681.2001.03491.x ◽

2001 ◽

Vol 28 (7) ◽

pp. 590-601 ◽

Cited By ~ 17

Author(s):

Joan Y Summy-Long ◽

Massako Kadekaro

Keyword(s):

Circumventricular Organs ◽

Neuroendocrine System ◽

Neuroendocrine Responses ◽

The Brain

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Circulating interleukin-6 induces fever through a STAT3-linked activation of COX-2 in the brain

AJP Regulatory Integrative and Comparative Physiology ◽

10.1152/ajpregu.00301.2006 ◽

2006 ◽

Vol 291 (5) ◽

pp. R1316-R1326 ◽

Cited By ~ 104

Author(s):

Christoph Rummel ◽

Christelle Sachot ◽

Stephen Poole ◽

Giamal N. Luheshi

Keyword(s):

Circumventricular Organs ◽

Significant Rise ◽

Infection And Inflammation ◽

Normal Sheep Serum ◽

Cox 2 ◽

Rate Limiting ◽

The Brain ◽

Dependent Pathway ◽

Nuclear Signal

Interleukin (IL)-6 is an important humoral mediator of fever following infection and inflammation and satisfies a number of criteria for a circulating pyrogen. However, evidence supporting such a role is diminished by the moderate or even absent ability of the recombinant protein to induce fever and activate the cyclooxygenase-2 (COX-2) pathway in the brain, a prerequisite step in the initiation and maintenance of fever. In the present study, we investigated the role of endogenous circulating IL-6 in a rodent model of localized inflammation, by neutralizing its action using a specific antiserum (IL-6AS). Rats were injected with LPS (100 μg/kg) or saline into a preformed air pouch in combination with an intraperitoneal injection of either normal sheep serum or IL-6AS (1.8 ml/rat). LPS induced a febrile response, which was accompanied by a significant rise in plasma IL-6 and nuclear STAT3 translocation in endothelial cells throughout the brain 2 h after treatment, including areas surrounding the sensory circumventricular organs and the median preoptic area (MnPO), important regions in mediating fever. These responses were abolished in the presence of the IL-6AS, which also significantly inhibited the LPS-induced upregulation of mRNA expression or immunoreactivity (IR) of the inducible form of COX, the rate-limiting enzyme for PGE2-synthesis. Interestingly, nuclear signal transducer and activator of transcription (STAT)3-positive cells colocalized with COX-2-IR, signifying that IL-6-activated cells are directly involved in PGE2 production. These observations suggest that IL-6 is an important circulating pyrogen that activates the COX-2-pathway in cerebral microvasculature, most likely through a STAT3-dependent pathway.

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Metabolomic and lipidomic changes triggered by lipopolysaccharide-induced systemic inflammation in transgenic APdE9 mice

Scientific Reports ◽

10.1038/s41598-021-92602-4 ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Elena Puris ◽

Štěpán Kouřil ◽

Lukáš Najdekr ◽

Sanna Loppi ◽

Paula Korhonen ◽

...

Keyword(s):

Disease Progression ◽

Brain Tissue ◽

Systemic Inflammation ◽

Metabolic Pathways ◽

Wild Type ◽

The Impact ◽

The Brain ◽

Lps Treatment

AbstractPeripheral infections followed by systemic inflammation may contribute to the onset of Alzheimer`s disease (AD) and accelerate the disease progression later in life. Yet, the impact of systemic inflammation on the plasma and brain tissue metabolome and lipidome in AD has not been investigated. In this study, targeted metabolomic and untargeted lipidomic profiling experiments were performed on the plasma, cortices, and hippocampi of wild-type (WT) mice and transgenic APdE9 mice after chronic lipopolysaccharide (LPS) treatment, as well as saline-treated APdE9 mice. The lipidome and the metabolome of these mice were compared to saline-treated WT animals. In the brain tissue of all three models, the lipidome was more influenced than the metabolome. The LPS-treated APdE9 mice had the highest number of changes in brain metabolic pathways with significant alterations in levels of lysine, myo-inositol, spermine, phosphocreatine, acylcarnitines and diacylglycerols, which were not observed in the saline-treated APdE9 mice. In the WT mice, the effect of the LPS administration on metabolome and lipidome was negligible. The study provided exciting information about the biochemical perturbations due to LPS-induced inflammation in the transgenic AD model, which can significantly enhance our understanding of the role of systemic inflammation in AD pathogenesis.

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