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Shionoya, K., Nilsson, A., Engström Ruud, L., Engblom, D. & Blomqvist, A. (2023). Melanocortin-4 receptors on neurons in the parabrachial nucleus mediate inflammation-induced suppression of food-seeking behavior. Brain, behavior, and immunity, 110, 80-84
Open this publication in new window or tab >>Melanocortin-4 receptors on neurons in the parabrachial nucleus mediate inflammation-induced suppression of food-seeking behavior
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2023 (English)In: Brain, behavior, and immunity, ISSN 0889-1591, E-ISSN 1090-2139, Vol. 110, p. 80-84Article in journal (Refereed) Published
Abstract [en]

Anorexia is a common symptom during infectious and inflammatory disease. Here we examined the role ofmelanocortin-4 receptors (MC4Rs) in inflammation-induced anorexia. Mice with transcriptional blockage of theMC4Rs displayed the same reduction of food intake following peripheral injection of lipopolysaccharide as wildtype mice but were protected against the anorexic effect of the immune challenge in a test in which fastedanimals were to use olfactory cues to find a hidden cookie. By using selective virus-mediated receptor reexpression we demonstrate that the suppression of the food-seeking behavior is subserved by MC4Rs in thebrain stem parabrachial nucleus, a central hub for interoceptive information involved in the regulation of foodintake. Furthermore, the selective expression of MC4R in the parabrachial nucleus also attenuated the bodyweight increase that characterizes MC4R KO mice. These data extend on the functions of the MC4Rs and showthat MC4Rs in the parabrachial nucleus are critically involved in the anorexic response to peripheral inflammation but also contribute to body weight homeostasis during normal conditions. 

Place, publisher, year, edition, pages
Elsevier, 2023
Keywords
Anorexia; Body weight homeostasis; Food-seeking; Inflammation; Melanocortin-4 receptors; Parabrachial nucleus
National Category
Neurosciences
Identifiers
urn:nbn:se:liu:diva-195497 (URN)10.1016/j.bbi.2023.02.014 (DOI)001011373300001 ()36813210 (PubMedID)2-s2.0-85149073489 (Scopus ID)
Note

Funding agencies: the Swedish Cancer Foundation (22 2338 Pj); Swedish Research Council (2020-00881, 2022-00952), Swedish Brain Foundation (FO2021-0010, FO2022-0114) and Knut och Alice Wallenbergs Stiftelse (WAF 2012).

Available from: 2023-06-21 Created: 2023-06-21 Last updated: 2024-01-10Bibliographically approved
Eskilsson, A., Shionoya, K. & Blomqvist, A. (2023). Prostaglandin production in brain endothelial cells during the initiation of fever. Communicative & Integrative Biology, 16(1), Article ID 2166237.
Open this publication in new window or tab >>Prostaglandin production in brain endothelial cells during the initiation of fever
2023 (English)In: Communicative & Integrative Biology, ISSN 1942-0889, E-ISSN 1942-0889, Vol. 16, no 1, article id 2166237Article in journal (Refereed) Published
Abstract [en]

The initiation of fever has been a matter of controversy. Based on observations of little or no induction of prostaglandin synthesizing enzymes in the brain during the first phase of fever it was suggested that fever is initiated by prostaglandin released into the circulation from cells in the liver and lungs. Here we show in the mouse that prostaglandin synthesis is rapidly induced in the brain after immune challenge. These data are consistent with our recent findings in functional experiments that prostaglandin production in brain endothelial cells is both necessary and sufficient for the generation of all phases of fever.

Place, publisher, year, edition, pages
Informa UK Limited, 2023
Keywords
Cyclooxygenase-2; brain vascular cells; lipopolysaccharide; microsomal prostaglandin E synthase-1; myeloid cells; prostaglandin E2
National Category
Neurosciences
Identifiers
urn:nbn:se:liu:diva-200822 (URN)10.1080/19420889.2023.2166237 (DOI)36644132 (PubMedID)
Funder
Swedish Cancer Society, 22 2338 PjThe Swedish Brain Foundation, FO2021-0010Swedish Research Council, 2020-00881
Available from: 2024-02-08 Created: 2024-02-08 Last updated: 2024-02-08
Shionoya, K., Eskilsson, A. & Blomqvist, A. (2022). Prostaglandin production selectively in brain endothelial cells is both necessary and sufficient for eliciting fever. Proceedings of the National Academy of Sciences of the United States of America, 119(43), Article ID e2122562119.
Open this publication in new window or tab >>Prostaglandin production selectively in brain endothelial cells is both necessary and sufficient for eliciting fever
2022 (English)In: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 119, no 43, article id e2122562119Article in journal (Refereed) Published
Abstract [en]

Fever is known to be elicited by prostaglandin E2 acting on the brain, but its origin has remained disputed. We show in mice that selective deletion of prostaglandin synthesis in brain endothelial cells, but not in neural cells or myeloid cells, abolished fever induced by intravenous administration of lipopolysaccharide and that selective rescue of prostaglandin synthesis in brain endothelial cells reinstated fever. These data demonstrate that prostaglandin production in brain endothelial cells is both necessary and sufficient for eliciting fever. 

Place, publisher, year, edition, pages
Washington, DC: National Academy of Sciences, 2022
Keywords
fever; cyclooxygenase-2; brain endothelial cells; microsomal prostaglandin E synthase-1
National Category
Cell and Molecular Biology
Identifiers
urn:nbn:se:liu:diva-189287 (URN)10.1073/pnas.2122562119 (DOI)000998802000018 ()36252026 (PubMedID)
Funder
Swedish Research Council, 2020-00881Swedish Cancer Society, 190304 PjThe Swedish Brain Foundation, FO2021-0010
Note

Funding: Swedish Research Council [2020-00881]; Swedish Brain Foundation [FO2021-0010]; Swedish Cancer Foundation [190304]

Available from: 2022-10-18 Created: 2022-10-18 Last updated: 2024-01-10Bibliographically approved
Nilsson, J. L. A., Mallet, C., Shionoya, K., Blomgren, A., Sundin, A. P., Grundemar, L., . . . Zygmunt, P. M. (2021). Paracetamol analogues conjugated by FAAH induce TRPV1-mediated antinociception without causing acute liver toxicity. European Journal of Medicinal Chemistry, 213, Article ID 113042.
Open this publication in new window or tab >>Paracetamol analogues conjugated by FAAH induce TRPV1-mediated antinociception without causing acute liver toxicity
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2021 (English)In: European Journal of Medicinal Chemistry, ISSN 0223-5234, E-ISSN 1768-3254, Vol. 213, article id 113042Article in journal (Refereed) Published
Abstract [en]

Paracetamol, one of the most widely used pain-relieving drugs, is deacetylated to 4-aminophenol (4-AP) that undergoes fatty acid amide hydrolase (FAAH)-dependent biotransformation into N-arachidonoylphenolamine (AM404), which mediates TRPV1-dependent antinociception in the brain of rodents. However, paracetamol is also converted to the liver-toxic metabolite N-acetyl-p-benzoquinone imine already at therapeutic doses, urging for safer paracetamol analogues. Primary amine analogues with chemical structures similar to paracetamol were evaluated for their propensity to undergo FAAH-dependent N-arachidonoyl conjugation into TRPV1 activators both in vitro and in vivo in rodents. The antinociceptive and antipyretic activity of paracetamol and primary amine analogues was examined with regard to FAAH and TRPV1 as well as if these analogues produced acute liver toxicity. 5-Amino-2-methoxyphenol (2) and 5-aminoindazole (3) displayed efficient target protein interactions with a dose-dependent antinociceptive effect in the mice formalin test, which in the second phase was dependent on FAAH and TRPV1. No hepatotoxicity of the FAAH substrates transformed into TRPV1 activators was observed. While paracetamol attenuates pyrexia via inhibition of brain cyclooxygenase, its antinociceptive FAAH substrate 4-AP was not antipyretic, suggesting separate mechanisms for the antipyretic and antinociceptive effect of paracetamol. Furthermore, compound 3 reduced fever without a brain cyclooxygenase inhibitory action. The data support our view that analgesics and antipyretics without liver toxicity can be derived from paracetamol. Thus, research into the molecular actions of paracetamol could pave the way for the discovery of analgesics and antipyretics with a better benefit-to-risk ratio. (C) 2020 The Author(s). Published by Elsevier Masson SAS.

Place, publisher, year, edition, pages
ELSEVIER FRANCE-EDITIONS SCIENTIFIQUES MEDICALES ELSEVIER, 2021
Keywords
Paracetamol; Acetaminophen; TRP channel; TRPV1; FAAH; Analgesic; Pain; Fever
National Category
Pharmacology and Toxicology
Identifiers
urn:nbn:se:liu:diva-175088 (URN)10.1016/j.ejmech.2020.113042 (DOI)000629626600004 ()33257173 (PubMedID)
Note

Funding Agencies|Medical Faculty of Lund University [ALFSKANE-450751]; AFA Forsakring [140376]; Hjarnfonden [FO2019-0316]; Stiftelsen Olle Engkvist ByggmastareSwedish Research Council [189-290]; Swedish Research CouncilSwedish Research CouncilEuropean Commission [07879]; Royal Physiographic Society, Lund Sweden; Clermont Auvergne University, INSERM; Agence Nationale de la Recherche of the French government through the program "Investissements dAvenir (I-Site CAP 20-25)French National Research Agency (ANR)

Available from: 2021-04-21 Created: 2021-04-21 Last updated: 2023-08-22Bibliographically approved
Petkovic, F., Lazzarino, G., Engblom, D. & Blomqvist, A. (2020). IL-6R expressed on CNS vascular endothelial cells contributes to the development of experimental autoimmune encephalomyelitis in mice. Journal of Neuroimmunology, 342, Article ID 577211.
Open this publication in new window or tab >>IL-6R expressed on CNS vascular endothelial cells contributes to the development of experimental autoimmune encephalomyelitis in mice
2020 (English)In: Journal of Neuroimmunology, ISSN 0165-5728, E-ISSN 1872-8421, Vol. 342, article id 577211Article in journal (Refereed) Published
Abstract [en]

Experimental autoimmune encephalomyelitis (EAE) is the most common model for studying the molecular mechanisms of multiple sclerosis (MS). Here, we examined the CNS-restricted effects of classical interleukin (IL)6 signaling on the development of EAE, using mice with cell-type specific deletion of the IL-6 receptor (IL-6R). We found that IL-6R deletion in CNS vascular endothelial cells, but not in microglia, ameliorated symptoms of EAE. The milder clinical symptoms in the gene-deleted mice were associated with less demyelination and immune cell infiltration/activation, and lower mRNA levels of the cytokines IL-17 and IL-1 beta, as well as the cell adhesion molecules VCAM-1, ICAM-1 and ICAM-2 than what was seen in WT mice. These findings demonstrate that classical IL-6 signaling via endothelial cells of the CNS contributes substantially to the development of MS-like pathology, which should be taken into consideration when conceptualizing future therapeutic approaches.

Place, publisher, year, edition, pages
ELSEVIER, 2020
Keywords
Demyelination; Interleukin-6; Microglia; Multiple sclerosis; EAE; Endothelial cells
National Category
Neurosciences
Identifiers
urn:nbn:se:liu:diva-165639 (URN)10.1016/j.jneuroim.2020.577211 (DOI)000528048200007 ()32182451 (PubMedID)
Note

Postprint version uploaded on author’s personal web page: https://liu.se/medarbetare/andbl47

Funding Agencies|Swedish Research CouncilSwedish Research Council [2016-01301]; Swedish Brain Foundation [FO2019-0033]; Foundation for Parkinson Research at Linkoping University

Available from: 2020-05-11 Created: 2020-05-11 Last updated: 2024-01-10
Zajdel, J., Zager, A., Blomqvist, A., Engblom, D. & Shionoya, K. (2019). Acute maternal separation potentiates the gene expression and corticosterone response induced by inflammation. Brain, behavior, and immunity, 77, 141-149
Open this publication in new window or tab >>Acute maternal separation potentiates the gene expression and corticosterone response induced by inflammation
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2019 (English)In: Brain, behavior, and immunity, ISSN 0889-1591, E-ISSN 1090-2139, Vol. 77, p. 141-149Article in journal (Refereed) Published
Abstract [en]

Maternal care is crucial for infants and profoundly affects their responses to different kinds of stressors. Here, we examined how maternal separation affects inflammatory gene expression and the corticosterone response to an acute immune challenge induced by lipopolysaccharide (LPS; 40 µg/kg ip) in mouse pups, 8–9 days old. Maternal separation initially attenuated LPS-induced hypothalamic pro-inflammatory gene expression, but later, at 3 h after immune challenge, robustly augmented such gene expression and increased serum corticosterone levels. Providing the pups with a warm and soft object prevented the separation-induced augmented hypothalamic-pituitary-adrenal (HPA)-axis response. It also prevented the potentiated induction of some, but not all, inflammatory genes to a similar extent as did the dam. Our results show that maternal separation potentiates the inflammatory response and the resulting HPA-axis activation, which may have detrimental effects if separation is prolonged or repeated.

Place, publisher, year, edition, pages
Elsevier, 2019
Keywords
Lipopolysaccharide, Hypothalamus, Cytokines, Inflammation, Maternal separation, Corticosterone
National Category
Pharmacology and Toxicology Developmental Biology Medical Biotechnology Immunology
Identifiers
urn:nbn:se:liu:diva-154886 (URN)10.1016/j.bbi.2018.12.016 (DOI)000461412600016 ()30590109 (PubMedID)2-s2.0-85059128986 (Scopus ID)
Available from: 2019-03-04 Created: 2019-03-04 Last updated: 2024-01-10Bibliographically approved
Klawonn, A., Fritz, M., Nilsson, A., Bonaventura, J., Shionoya, K., Mirrasekhian, E., . . . Engblom, D. (2018). Motivational valence is determined by striatal melanocortin 4 receptors. Journal of Clinical Investigation, 128(7), 3160-3170
Open this publication in new window or tab >>Motivational valence is determined by striatal melanocortin 4 receptors
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2018 (English)In: Journal of Clinical Investigation, ISSN 0021-9738, E-ISSN 1558-8238, Vol. 128, no 7, p. 3160-3170Article in journal (Refereed) Published
Abstract [en]

It is critical for survival to assign positive or negative valence to salient stimuli in a correct manner. Accordingly, harmful stimuli and internal states characterized by perturbed homeostasis are accompanied by discomfort, unease, and aversion. Aversive signaling causes extensive suffering during chronic diseases, including inflammatory conditions, cancer, and depression. Here, we investigated the role of melanocortin 4 receptors (MC4Rs) in aversive processing using genetically modified mice and a behavioral test in which mice avoid an environment that they have learned to associate with aversive stimuli. In normal mice, robust aversions were induced by systemic inflammation, nausea, pain, and. opioid receptorinduced dysphoria. In sharp contrast, mice lacking MC4Rs displayed preference or indifference toward the aversive stimuli. The unusual flip from aversion to reward in mice lacking MC4Rs was dopamine dependent and associated with a change from decreased to increased activity of the dopamine system. The responses to aversive stimuli were normalized when MC4Rs were reexpressed on dopamine D1 receptor-expressing cells or in the striatum of mice otherwise lacking MC4Rs. Furthermore, activation of arcuate nucleus proopiomelanocortin neurons projecting to the ventral striatum increased the activity of striatal neurons in an MC4R-dependent manner and elicited aversion. Our findings demonstrate that melanocortin signaling through striatal MC4Rs is critical for assigning negative motivational valence to harmful stimuli.

Place, publisher, year, edition, pages
AMER SOC CLINICAL INVESTIGATION INC, 2018
National Category
Neurosciences
Identifiers
urn:nbn:se:liu:diva-149861 (URN)10.1172/JCI97854 (DOI)000437234600044 ()29911992 (PubMedID)
Note

Funding Agencies|European Research Council; Swedish Medical Research Council; Knut and Alice Wallenberg Foundation; Swedish Brain foundation; County Council of Ostergotland; National Institute on Drug Abuse Intramural Research Program [ZIA000069]; Lars Hiertas Minne Foundation

Available from: 2018-08-02 Created: 2018-08-02 Last updated: 2024-01-10
Blomqvist, A. & Engblom, D. (2018). Neural Mechanisms of Inflammation-Induced Fever. The Neuroscientist, 24(4), 381-399
Open this publication in new window or tab >>Neural Mechanisms of Inflammation-Induced Fever
2018 (English)In: The Neuroscientist, ISSN 1073-8584, E-ISSN 1089-4098, Vol. 24, no 4, p. 381-399Article, review/survey (Refereed) Published
Abstract [en]

Fever is a common symptom of infectious and inflammatory disease. It is well-established that prostaglandin E-2 is the final mediator of fever, which by binding to its EP3 receptor subtype in the preoptic hypothalamus initiates thermogenesis. Here, we review the different hypotheses on how the presence of peripherally released pyrogenic substances can be signaled to the brain to elicit fever. We conclude that there is unequivocal evidence for a humoral signaling pathway by which proinflammatory cytokines, through their binding to receptors on brain endothelial cells, evoke fever by eliciting prostaglandin E-2 synthesis in these cells. The evidence for a role for other signaling routes for fever, such as signaling via circumventricular organs and peripheral nerves, as well as transfer into the brain of peripherally synthesized prostaglandin E-2 are yet far from conclusive. We also review the efferent limb of the pyrogenic pathways. We conclude that it is well established that prostaglandin E-2 binding in the preoptic hypothalamus produces fever by disinhibition of presympathetic neurons in the brain stem, but there is yet little understanding of the mechanisms by which factors such as nutritional status and ambient temperature shape the response to the peripheral immune challenge.

Place, publisher, year, edition, pages
Sage Publications, 2018
Keywords
fever; cytokines; prostaglandin E2; brain endothelial cells; median preoptic nucleus; EP3 receptors
National Category
Neurosciences
Identifiers
urn:nbn:se:liu:diva-150242 (URN)10.1177/1073858418760481 (DOI)000439623500009 ()29557255 (PubMedID)2-s2.0-85044398777 (Scopus ID)
Note

Funding Agencies|Swedish Medical Research Council [07879, 20725]; European Research Council; Knut and Alice Wallenberg foundation; Swedish Brain Foundation; Swedish Cancer Foundation [213/692]; County Council of Ostergotland

Available from: 2018-08-17 Created: 2018-08-17 Last updated: 2024-01-10Bibliographically approved
Mirrasekhian, E., Nilsson, J. L. Å., Shionoya, K., Blomgren, A., Zygmunt, P. M., Engblom, D., . . . Blomqvist, A. (2018). The antipyretic effect of paracetamol occurs independent of transient receptor potential ankyrin 1–mediated hypothermia and is associated with prostaglandin inhibition in the brain. The FASEB Journal
Open this publication in new window or tab >>The antipyretic effect of paracetamol occurs independent of transient receptor potential ankyrin 1–mediated hypothermia and is associated with prostaglandin inhibition in the brain
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2018 (English)In: The FASEB Journal, ISSN 0892-6638, E-ISSN 1530-6860Article in journal (Refereed) Published
Abstract [en]

The mode of action of paracetamol (acetaminophen), which is widely used for treating pain and fever, has remained obscure, but may involve several distinct mechanisms, including cyclooxygenase inhibition and transient receptor potential ankyrin 1 (TRPA1) channel activation, the latter being recently associated with paracetamol?s propensity to elicit hypothermia at higher doses. Here, we examined whether the antipyretic effect of paracetamol was due to TRPA1 activation or cyclooxygenase inhibition. Treatment of wild-type and TRPA1 knockout mice rendered febrile by immune challenge with LPS with a dose of paracetamol that did not produce hypothermia (150 mg/kg) but is known to be analgetic, abolished fever in both genotypes. Paracetamol completely suppressed the LPS-induced elevation of prostaglandin E2 in the brain and also reduced the levels of several other prostanoids. The hypothermia induced by paracetamol was abolished in mice treated with the electrophile-scavenger N-acetyl cysteine. We conclude that paracetamol?s antipyretic effect in mice is dependent on inhibition of cyclooxygenase activity, including the formation of pyrogenic prostaglandin E2, whereas paracetamol-induced hypothermia likely is mediated by the activation of TRPA1 by electrophilic metabolites of paracetamol, similar to its analgesic effect in some experimental paradigms.?Mirrasekhian, E., Nilsson, J. L. Å., Shionoya, K., Blomgren, A., Zygmunt, P. M., Engblom, D., Högestätt, E. D., Blomqvist, A. The antipyretic effect of paracetamol occurs independent of transient receptor potential ankyrin 1?mediated hypothermia and is associated with prostaglandin inhibition in the brain.

Place, publisher, year, edition, pages
Federation of American Societies for Experimental Biology, 2018
National Category
Pharmacology and Toxicology
Identifiers
urn:nbn:se:liu:diva-148562 (URN)10.1096/fj.201800272R (DOI)000447972500045 ()29738273 (PubMedID)
Note

Funding agencies: Swedish Medical Research Council [20725, 07879, 2014-3801]; European Research Council (ERC) Starting Grant; Knut and Alice Wallenberg Foundation; Swedish Brain Foundation; Swedish Cancer Foundation [16/0572]; County Council of Ostergotland; Medical Facult

Available from: 2018-06-13 Created: 2018-06-13 Last updated: 2024-01-10Bibliographically approved
Nilsson, A., Wilhelms, D., Mirrasekhian, E., Jaarola, M., Blomqvist, A. & Engblom, D. (2017). Inflammation-induced anorexia and fever are elicited by distinct prostaglandin dependent mechanisms, whereas conditioned taste aversion is prostaglandin independent.. Brain, behavior, and immunity, 61, 236-243, Article ID S0889-1591(16)30549-9.
Open this publication in new window or tab >>Inflammation-induced anorexia and fever are elicited by distinct prostaglandin dependent mechanisms, whereas conditioned taste aversion is prostaglandin independent.
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2017 (English)In: Brain, behavior, and immunity, ISSN 0889-1591, E-ISSN 1090-2139, Vol. 61, p. 236-243, article id S0889-1591(16)30549-9Article in journal (Refereed) Published
Abstract [en]

Systemic inflammation evokes an array of brain-mediated responses including fever, anorexia and taste aversion. Both fever and anorexia are prostaglandin dependent but it has been unclear if the cell-type that synthesizes the critical prostaglandins is the same. Here we show that pharmacological inhibition or genetic deletion of cyclooxygenase (COX)-2, but not of COX-1, attenuates inflammation-induced anorexia. Mice with deletions of COX-2 selectively in brain endothelial cells displayed attenuated fever, as demonstrated previously, but intact anorexia in response to peripherally injected lipopolysaccharide (10μg/kg). Whereas intracerebroventricular injection of a cyclooxygenase inhibitor markedly reduced anorexia, deletion of COX-2 selectively in neural cells, in myeloid cells or in both brain endothelial and neural cells had no effect on LPS-induced anorexia. In addition, COX-2 in myeloid and neural cells was dispensable for the fever response. Inflammation-induced conditioned taste aversion did not involve prostaglandin signaling at all. These findings collectively show that anorexia, fever and taste aversion are triggered by distinct routes of immune-to-brain signaling.

Place, publisher, year, edition, pages
Elsevier, 2017
Keywords
Anorexia, Conditioned place aversion, Cyclooxygenase, Fever, Inflammation, Lipopolysaccharide
National Category
Immunology in the medical area
Identifiers
urn:nbn:se:liu:diva-136127 (URN)10.1016/j.bbi.2016.12.007 (DOI)000395365900026 ()27940259 (PubMedID)
Note

Funding agencies: Swedish Medical Research Council [20725, 07879]; European Research Council; Knut and Alice Wallenberg foundation; Swedish Brain Foundation; Swedish Cancer Foundation [213/692]; County Council of Ostergotland

Available from: 2017-03-28 Created: 2017-03-28 Last updated: 2024-01-10Bibliographically approved
Organisations
Identifiers
ORCID iD: ORCID iD iconorcid.org/0000-0002-6928-4473

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