Expression of myeloid differentiation factor 88 in neurons is not requisite for the induction of sickness behavior by interleukin-1β

Braun, Theodore P.; Grossberg, Aaron J.; Veleva-Rotse, Biliana O.; Maxson, Julia E.; Szumowski, Marek; Barnes, Anthony P.; Marks, Daniel L.

doi:10.1186/1742-2094-9-229

Cited by 26 publications

(27 citation statements)

References 31 publications

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“…The data from our previous work and that from other groups demonstrates a unique role for hypothalamic MyD88 signaling in the illness response to several important PAMPs, and in the inflammatory amplification and cytokine signaling observed in the hypothalamus during systemic inflammation 17 31 . Furthermore, in vitro stimulation of TLR3KO microglia with poly (I:C) results in substantial cytokine release and activation of downstream MAPK signaling, albeit with delayed kinetics relative to WT microglia 24 .…”

Section: Discussionmentioning

confidence: 62%

“…Prior studies demonstrate that in response to both peripheral and central immune challenge, a pro-inflammatory response is generated within the CNS, with particularly robust inflammation noted within the MBH 15 16 18 31 . In particular, the local expression and release of IL-1β within the hypothalamus is critical for the induction of sickness behaviors 1 17 .…”

Section: Resultsmentioning

confidence: 99%

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A distinct brain pathway links viral RNA exposure to sickness behavior

Zhu

Levasseur

Michaelis

et al. 2016

Sci Rep

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Sickness behaviors and metabolic responses to invading pathogens are common to nearly all types of infection. These responses evolved to provide short-term benefit to the host to ward off infection, but impact on quality of life, and when prolonged lead to neurodegeneration, depression, and cachexia. Among the major infectious agents, viruses most frequently enter the brain, resulting in profound neuroinflammation. We sought to define the unique features of the inflammatory response in the brain to these infections. We demonstrate that the molecular pathway defining the central response to dsRNA is distinct from that found in the periphery. The behavioral and physical response to the dsRNA mimetic poly I:C is dependent on signaling via MyD88 when it is delivered centrally, whereas this response is mediated via the TRIF pathway when delivered peripherally. We also define the likely cellular candidates for this MyD88-dependent step. These findings suggest that symptom management is possible without ameliorating protective antiviral immune responses.

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Section: Discussionmentioning

confidence: 62%

Section: Resultsmentioning

confidence: 99%

A distinct brain pathway links viral RNA exposure to sickness behavior

Zhu

Levasseur

Michaelis

et al. 2016

Sci Rep

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“…A number of previous studies have found that TLRs in the spinal cord played an important role in the model of neuropathic pain and nerve injury, in which microglia and astrocytes produced proinflammatory cytokines by activating TLRs [18–20]. Nociceptors of DRG that express TLRs or IL-1R are also activated by LPS or inflammatory cytokine interleukin-1β, inducing pain hypersensitivity [5, 18–22]. Recent publications show that MyD88, adaptor protein of TLRs and IL-1R, is also found in the expression in DRG and spinal cord [18–20].…”

Section: Introductionmentioning

confidence: 99%

Suppression of MyD88-dependent signaling alleviates neuropathic pain induced by peripheral nerve injury in the rat

Liu

Wang

Qiu

et al. 2017

J Neuroinflammation

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BackgroundMyD88 is the adaptor protein of MyD88-dependent signaling pathway of TLRs and IL-1 receptor and regulates innate immune response. However, it was not clear whether and how MyD88 and related signaling pathways in the dorsal root ganglion (DRG) and spinal dorsal horn (SDH) are involved in neuropathic pain.MethodsChronic constriction injury (CCI) was used to induce neuropathic pain in the rat. The expression of MyD88, TRIF, IBA1, and GFAP was detected with immunofluorescent staining and Western blot. The expression of interleukin-1 beta (IL-1β), high mobility group box 1 (HMGB1), NF-κB-p65, phosphorylated NF-κB-p65, ERK, phosphorylated ERK, and tumor necrosis factor-alpha (TNF-α) was detected with Western blot. Pain-related behavioral effects of MyD88 homodimerization inhibitory peptide (MIP) were accessed up to 3 weeks after intrathecal administration.ResultsPeripheral nerve injury significantly increased the protein level of MyD88 in the DRG and SDH, but had no effect on TRIF. MyD88 was found partly distributed in the nociceptive neurons in the DRGs and the astrocytes and microglia in the SDH. HMGB1 and IL-1β were also found upregulated in nociceptive pathways of CCI rats. Intrathecal application of MIP significantly alleviated mechanical and thermal hyperalgesia in the CCI rats and also reversed CCI-induced upregulation of MyD88 in both DRG and SDH. Further investigation revealed that suppression of MyD88 protein reduced the release of TNF-α and glial activation in the SDH in the CCI rats.ConclusionsMyD88-dependent TIR pathway in the DRG and SDH may play a role in CCI-induced neuropathic pain. MyD88 might serve as a potential therapeutic target for neuropathic pain.Electronic supplementary materialThe online version of this article (doi:10.1186/s12974-017-0822-9) contains supplementary material, which is available to authorized users.

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“…Sickness responses are coordinated sets of adaptive behavioral changes including loss of appetite, hypoactivity, and hyperthermia during the course of human diseases such as cancer, acquired immune deficiency syndrome (AIDS), tuberculosis, and renal failure 4 . Although hypothalamic inflammation has been recognized as a prominent component of sickness responses 5 6 , the pathophysiologic mechanisms of sickness symptoms are poorly understood.…”

mentioning

confidence: 99%

Hypothalamic TLR2 triggers sickness behavior via a microglia-neuronal axis

Jin

Kim

Park

et al. 2016

Sci Rep

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Various pathophysiologic mechanisms leading to sickness behaviors have been proposed. For example, an inflammatory process in the hypothalamus has been implicated, but the signaling modalities that involve inflammatory mechanisms and neuronal circuit functions are ill-defined. Here, we show that toll-like receptor 2 (TLR2) activation by intracerebroventricular injection of its ligand, Pam3CSK4, triggered hypothalamic inflammation and activation of arcuate nucleus microglia, resulting in altered input organization and increased activity of proopiomelanocortin (POMC) neurons. These animals developed sickness behavior symptoms, including anorexia, hypoactivity, and hyperthermia. Antagonists of nuclear factor kappa B (NF-κB), cyclooxygenase pathway and melanocortin receptors 3/4 reversed the anorexia and body weight loss induced by TLR2 activation. These results unmask an important role of TLR2 in the development of sickness behaviors via stimulation of hypothalamic microglia to promote POMC neuronal activation in association with hypothalamic inflammation.A growing body of evidence indicates that an inflammatory process in the hypothalamus is one of the major causes of dysfunctions in energy metabolism. In particular, previous studies have focused on events of chronic inflammation, which is an important pathologic element leading to metabolic syndromes 1,2 . However, the significance of acute hypothalamic inflammation in sickness behaviors has been relatively ignored even though it is closely correlated with human diseases such as infection and cachexia 3 . Sickness responses are coordinated sets of adaptive behavioral changes including loss of appetite, hypoactivity, and hyperthermia during the course of human diseases such as cancer, acquired immune deficiency syndrome (AIDS), tuberculosis, and renal failure 4 . Although hypothalamic inflammation has been recognized as a prominent component of sickness responses 5,6 , the pathophysiologic mechanisms of sickness symptoms are poorly understood.Toll-like receptors (TLRs) are key components of the innate immune system through their role in the recognition of a variety of pathogens and inflammatory signals 7 . Recently, it has been proposed that perturbation of metabolic controls is closely associated with the function of TLRs as inflammatory modulators [8][9][10] . In the development of diet-or ageing-induced obesity, the function of TLRs in the neural cells is thought to be as important as their impact on peripheral organs 11,12 . Nevertheless, it remains unclear whether TLRs participate in the development of sickness behaviors governed by hypothalamic neural circuits. Therefore, in this study, we interrogated the role of hypothalamic TLR2 in the development of sickness behaviors caused by acute hypothalamic inflammation.We found that intracerebroventricular (icv) injection of the TLR2 ligand Pam3CSK4 led to sickness responses including anorexia, hypoactivity, and hyperthermia through stimulation of inflammatory processes in the hypothalamus. In addition, we observe...

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Expression of myeloid differentiation factor 88 in neurons is not requisite for the induction of sickness behavior by interleukin-1β

Cited by 26 publications

References 31 publications

A distinct brain pathway links viral RNA exposure to sickness behavior

A distinct brain pathway links viral RNA exposure to sickness behavior

Suppression of MyD88-dependent signaling alleviates neuropathic pain induced by peripheral nerve injury in the rat

Hypothalamic TLR2 triggers sickness behavior via a microglia-neuronal axis

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