Depletion of microglia and macrophages with clodronate liposomes attenuates zymosan-induced Fos expression and hypothermia in the adult mouse

Takagi, Shun; Murayama, Shotaro; Torii, Katsuhiro; Takemura-Morita, Shoko; Kurganov, Erkin; Nagaoka, Sumiharu; Wanaka, Akio; Miyata, Seiji

doi:10.1016/j.jneuroim.2020.577244

Cited by 17 publications

(21 citation statements)

References 54 publications

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“…Peripherally administered LPS and zymosan reach TLR4 on astrocytes and TLR2 on microglia and/or macrophages in the OVLT 13,43 . TRPM8-expressing neurons are specifically localized at the POA and LS 30 .…”

Section: Discussionmentioning

confidence: 99%

“…More specifically, the intraperitoneal administration of the TLR4 agonist, lipopolysaccharide (LPS), was shown to induce fever or hypothermia in a dose-dependent manner: a low dose of 50~100 μg/kg induced fever, whereas a high dose of more than 2.5 mg/kg caused hypothermia 10,11 . The intraperitoneal administration of a low dose of the TLR2 agonist zymosan of 1~10 mg/kg induced fever 12 , whereas a high dose of more than 50 mg/kg caused hypothermia 13 . Therefore, the two thermoregulatory responses are complementary strategies of survival in infection-induced inflammation; however, limited information is currently available on the switching mechanism between fever and hypothermia.…”

Section: Introductionmentioning

confidence: 99%

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Role of TRPM8 in Switching Between Fever and Hypothermia in Adult Mice During Endotoxin-Induced Inflammation

Shiraki

Horikawa

Fujimoto

et al. 2020

Preprint

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Transient receptor potential melastatin 8 (TRPM8) functions in the sensing of noxious and innocuous colds; however, its significance in pathogen-induced thermoregulation and inflammation remains unclear. In the present study, we investigated the role of TRPM8 in the regulation of endotoxin-induced body temperature control and inflammation. The peripheral administration of low-dose LPS or zymosan generated fever in wild-type (WT) mice and hypothermia in TRPM8 knockout (KO) animals. TRPM8 KO mice exhibited severe hypothermia and sickness responses following the peripheral administration of high-dose LPS. An intracerebroventricular injection of LPS and interleukin-1ß (Il-1ß) elicited hypothermia in TRPM8 KO mice, in contrast to fever in WT animals, whereas that of prostaglandin E2 induced normal fever. Fos immunohistochemistry showed the stronger activation of hypothalamic thermoregulation-associated nuclei following the peripheral administration of low-dose LPS. Therefore, TRPM8 is necessary for switching between fever and hypothermia during endotoxin-induced inflammation.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Role of TRPM8 in Switching Between Fever and Hypothermia in Adult Mice During Endotoxin-Induced Inflammation

Shiraki

Horikawa

Fujimoto

et al. 2020

Preprint

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“…7 Numerous studies have found that the population of macrophages is significantly increased during the active phase of IBD and plays essential roles in DSS-induced colitis, showing promise as targets for potential novel therapies to treat IBD. 8 Clophosome, neutral clodronate liposomes (CNC), is a wellknown macrophage depletion agent whose effective constituent is liposome-encapsulated clodronate from the bisphosphonate family. 9 Due to its high efficiency and nontoxicity, clodronate has been widely used in the clinical treatment of osteometabolic disorders, such as osteoporosis and arthritis.…”

Section: Proinflammatory Cytokines Can Further Trigger Inflammatory Responses By Promoting the Proliferation And Differentiation Of T Celmentioning

confidence: 99%

“…Proinflammatory cytokines can further trigger inflammatory responses by promoting the proliferation and differentiation of T cells, contributing to the occurrence of acquired immunity 7 . Numerous studies have found that the population of macrophages is significantly increased during the active phase of IBD and plays essential roles in DSS‐induced colitis, showing promise as targets for potential novel therapies to treat IBD 8 …”

Section: Introductionmentioning

confidence: 99%

Clophosome alleviate dextran sulphate sodium‐induced colitis by regulating gut immune responses and maintaining intestinal integrity in mice

Tian

Wang

et al. 2021

Clin Exp Pharma Physio

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Inflammatory bowel disease (IBD) is a chronic progressive disorder characterized by complicated gastrointestinal inflammation. Research on therapeutic agents is still urgent due to the lack of satisfactory treatments. Gut macrophages are considered to be predominant in excessive inflammatory responses. Thus, we aimed to investigate whether depletion of macrophages would have a beneficial effect on IBD and could be a potential therapeutic strategy. In this study, we established a 12‐day Dextran sodium sulphate (DSS)‐induced colitis mouse model and determined the effect of the macrophage depletion agent Clophosome (neutral clodronate liposomes; CNC). The results showed that CNC significantly alleviated the symptoms of colitis, as demonstrated by greater weight gain, decreased disease activity index (DAI) scores, and lower histopathological damage scores, as well was reduced levels of the proinflammatory cytokines interleukin (IL)‐6 and tumour necrosis factor (TNF)‐α. To investigate T cell subsets, cells were isolated from the lamina propria and cultured to analyse the expression of IL‐17A, interferon (IFN)‐γ and Foxp3 in CD4+ cells by flow cytometry. The data showed that during the process of colitis, the frequencies of CD4+IL‐17A+ T cells were significantly increased. Notably, CNC treatment markedly reduced the population of CD4+IL‐17A+ T cells, especially CD4+IL‐17A+IFN‐γ+ T cells. Furthermore, intestinal barrier integrity, as assessed by immunostaining of mucin and tight junction proteins, was severely disrupted in colitis. CNC improved the intestinal barrier by enhancing the expression of muc‐2 and occludin. In summary, our findings demonstrated that CNC successfully ameliorated DSS‐induced colitis and that its effect may be associated with inhibiting inflammatory responses and maintaining intestinal integrity.

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“…The intraperitoneal administration of the TLR4 agonist, lipopolysaccharide (LPS), was shown to induce fever or hypothermia in mouse depending on dose: a low dose of 50–100 μg/kg induced fever, whereas a high-dose of more than 2.5 mg/kg caused hypothermia ( Oka et al., 2003 ; Garami et al., 2018 ). The intraperitoneal administration of a low dose of the TLR2 agonist zymosan of 1–10 mg/kg induced fever ( Bastos-Pereira et al., 2014 ), whereas a high-dose of more than 50 mg/kg caused hypothermia ( Takagi et al., 2020 ). Therefore, the two thermoregulatory responses are complementary strategies of survival in infection-induced inflammation.…”

Section: Introductionmentioning

confidence: 99%

Role of TRPM8 in switching between fever and hypothermia in adult mice during endotoxin-induced inflammation

Shiraki

Horikawa

et al. 2021

Brain, Behavior, & Immunity - Health

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Transient receptor potential melastatin 8 (TRPM8) functions in the sensing of noxious and innocuous colds; however, its significance in pathogen-induced thermoregulation remains unclear. In the present study, we investigated the role of TRPM8 in the regulation of endotoxin-induced body temperature control. The peripheral administration of low-dose lipopolysaccharide (LPS) at 50 μg/kg generated fever in wild-type (WT) mice, whereas it caused hypothermia in TRPM8 knockout (KO) animals. LPS-induced sickness responses such as decrease in body weight, and food and water intake were not different between WT and TRPM8 KO mice. TRPM8 KO mice exhibited more severe hypothermia and lower locomotor activity following the peripheral administration of high-dose LPS at 5 mg/kg compared with WT ones. An intracerebroventricular (i.c.v.) injection of either LPS at 3.6 μg/kg or interleukin-1β at 400 ng/kg elicited hypothermia in TRPM8 KO mice, in contrast to fever in WT animals. The peripheral administration of zymosan at 3 mg/kg also induced hypothermia in contrast to fever in WT mice. An i.c.v. injection of prostaglandin E 2 at 16 or 160 nmol/kg induced normal fever in both WT and TRPM8 KO mice. Infrared thermography showed significant decline of the interscapular skin temperature that estimates temperature of the brown adipose tissue, regardless of no alteration of its temperature in WT animals. Fos immunohistochemistry showed stronger Fos activation of hypothalamic thermoregulation-associated nuclei in TRPM8 KO mice compared with WT animals following the peripheral administration of low-dose LPS. Therefore, the present study indicates that TRPM8 is necessary for switching between fever and hypothermia during endotoxin-induced inflammation.

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Depletion of microglia and macrophages with clodronate liposomes attenuates zymosan-induced Fos expression and hypothermia in the adult mouse

Cited by 17 publications

References 54 publications

Role of TRPM8 in Switching Between Fever and Hypothermia in Adult Mice During Endotoxin-Induced Inflammation

Role of TRPM8 in Switching Between Fever and Hypothermia in Adult Mice During Endotoxin-Induced Inflammation

Clophosome alleviate dextran sulphate sodium‐induced colitis by regulating gut immune responses and maintaining intestinal integrity in mice

Role of TRPM8 in switching between fever and hypothermia in adult mice during endotoxin-induced inflammation

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Depletion of microglia and macrophages with clodronate liposomes attenuates zymosan-induced Fos expression and hypothermia in the adult mouse

Cited by 17 publications

References 54 publications

Role of TRPM8&nbsp;in Switching Between Fever and Hypothermia in Adult Mice During Endotoxin-Induced Inflammation

Role of TRPM8&nbsp;in Switching Between Fever and Hypothermia in Adult Mice During Endotoxin-Induced Inflammation

Clophosome alleviate dextran sulphate sodium‐induced colitis by regulating gut immune responses and maintaining intestinal integrity in mice

Role of TRPM8 in switching between fever and hypothermia in adult mice during endotoxin-induced inflammation

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Role of TRPM8 in Switching Between Fever and Hypothermia in Adult Mice During Endotoxin-Induced Inflammation

Role of TRPM8 in Switching Between Fever and Hypothermia in Adult Mice During Endotoxin-Induced Inflammation