Activation of GPR37 in macrophages confers protection against infection-induced sepsis and pain-like behaviour in mice

Bang, Sangsu; Donnelly, Christopher R.; Luo, Xin; Toro-Moreno, Maria; Tao, Xueshu; Wang, Zilong; Chandra, Sharat; Bortsov, Andrey V.; Derbyshire, Emily R.; Ji, Ru-Rong

doi:10.1038/s41467-021-21940-8

Cited by 56 publications

(50 citation statements)

References 58 publications

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“…The dysfunction or death of these cells are closely involved in sepsis-AKI (22)(23)(24). During the host's defense against infection, macrophages play a central role in innate immunity (25,26), recognizing pathogen-associated molecular patterns (PAMPs) and/or host-derived damage-associated molecular patterns (DAMPs) through pattern recognition receptors (27,28). PAMPs and/or DAMPs released from damaged tissues activate and promote the pro-inflammatory phenotype (M1) of macrophages, leading to the release of pro-inflammatory cytokines such as interleukin (IL)-1, IL-6, tumor necrosis factor-α (TNF-α), chemokines and reactive oxygen species (ROS), which cause damage to the kidney tissue (29,30).…”

Section: Macrophages Vascular Endothelial Cells and Renal Tubular Epithelial Cells Are Involved In Sepsis-akimentioning

confidence: 99%

The Programmed Cell Death of Macrophages, Endothelial Cells, and Tubular Epithelial Cells in Sepsis-AKI

Wang

et al. 2021

Front. Med.

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Sepsis is a systemic inflammatory response syndrome caused by infection, following with acute injury to multiple organs. Sepsis-induced acute kidney injury (AKI) is currently recognized as one of the most severe complications related to sepsis. The pathophysiology of sepsis-AKI involves multiple cell types, including macrophages, vascular endothelial cells (ECs) and renal tubular epithelial cells (TECs), etc. More significantly, programmed cell death including apoptosis, necroptosis and pyroptosis could be triggered by sepsis in these types of cells, which enhances AKI progress. Moreover, the cross-talk and connections between these cells and cell death are critical for better understanding the pathophysiological basis of sepsis-AKI. Mitochondria dysfunction and oxidative stress are traditionally considered as the leading triggers of programmed cell death. Recent findings also highlight that autophagy, mitochondria quality control and epigenetic modification, which interact with programmed cell death, participate in the damage process in sepsis-AKI. The insightful understanding of the programmed cell death in sepsis-AKI could facilitate the development of effective treatment, as well as preventive methods.

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Section: Macrophages Vascular Endothelial Cells and Renal Tubular Epithelial Cells Are Involved In Sepsis-akimentioning

confidence: 99%

The Programmed Cell Death of Macrophages, Endothelial Cells, and Tubular Epithelial Cells in Sepsis-AKI

Wang

et al. 2021

Front. Med.

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“…Furthermore, previous studies reported a reduction of glial reaction upon local injection of PD 1 in mouse models of sciatic nerve transection, suggesting that the latter SPM might act through multiple pathways, yet to be fully understood (Xu et al, 2013). Consistently, GPR37 −/− mice display enhanced mechanical and cold allodynia, as well as thermal hyperalgesia during bacterial infections, while macrophages primed with GPR37 agonists reduce mechanical allodynia in the same GPR37 −/− mice (Bang et al, 2021). Also PD 1 has been demonstrated to counteract neuropathic pain by directly targeting sensory nociception via TRPV1 inhibition in DRG neurons (Park et al, 2011a), and by reversing nerve injuryinduced spinal cord synaptic plasticity in nerve trauma (Xu et al, 2013).…”

Section: Dha-derived Spmsmentioning

confidence: 96%

Role of Specialized Pro-Resolving Mediators in Neuropathic Pain

et al. 2021

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Inflammation and neuroinflammation are critical mechanisms in the generation of neuropathic pain that is experienced in several chronic diseases. The aberrant inflammation that triggers this pathophysiologic process can be tracked down to an exacerbated immune response, which establishes a vicious cycle and continuously recruits inflammatory cells by inducing chronic tissue damage. Recently, impairment of the cellular and molecular machinery orchestrated by specialized pro-resolving mediators (SPMs)—i.e., endogenous lipids termed resolvins, protectins, maresins, and lipoxins that confine the inflammatory cascades in space and time during the “resolution of inflammation”–has emerged as a crucial event in the derangement of the inflammatory homeostasis and the onset of chronic inflammation and pain. Indeed, a deviant inflammatory response that is not adequately controlled by the resolution network leads to the overproduction of pro-inflammatory eicosanoids that, opposite to SPMs, lead to neuropathic pain. Interestingly, in the last two decades convincing evidence has demonstrated that SPMs antagonize the in vivo activity of pro-inflammatory eicosanoids and, overall, exert potent anti-hyperalgesic effects in a number of pain-associated paradigms of disease, such as arthritis and chemotherapy-induced peripheral neuropathy, as well as in many experimental models of pain like mechanical allodynia, chemical pain, heat hypersensitivity and phase 1 and 2 inflammatory pain. Of note, accumulated evidence supports a synergy between SPMs and other signalling pathways, such as those mediated by transient receptor potential (TRP) channels and those triggered by opioid receptors, suggesting that the cascade of events where inflammation and pain perception take part might be ways more intricated than originally expected. Here, we aim at presenting a state-of-the-art view of SPMs, their metabolism and signalling, in the context of cellular and molecular pathways associated to neuropathic pain.

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“…The innate behaviors of LPS-induce mice in automated home-cage monitoring should be carefully interpreted as behavioral pain since LPS was administered intraperitoneally. Although intraperitoneal administration of LPS has been devised in several pain models, such as sepsis-associated pain, musculoskeletal pain, and visceral pain [11,[18][19][20]35], the intraperitoneal administration of LPS can cause a systemic immune response leading to the development of sickness behaviors. Sickness behaviors produced by intraperitoneal administration of LPS include fatigue, depressive-like behavior, feeding behavior, anxiolytic-like behavior, changes in sleep-wake and feeding behaviors, weight loss, fever, and pain-like behaviors [8][9][10][11][12][13].…”

Section: Plos Onementioning

confidence: 99%

“…At the mechanistic levels both sickness and painlike behaviors are associated with increased pro-inflammatory mediators [8,17]. Therefore, the use of endotoxin has been recently introduced as a model for the study of inflammatory pain in both animals and humans [18][19][20][21][22][23][24][25]. The administration of LPS produces a significant expression of proinflammatory mediators, like cytokines, chemokines, cyclooxygenase-2 (COX-2), and nitric oxide through activation of toll-like receptor 4 (TLR4) via modulating immune cells [26][27][28].…”

Section: Introductionmentioning

confidence: 99%

Automated home-cage monitoring as a potential measure of sickness behaviors and pain-like behaviors in LPS-treated mice

et al. 2021

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The use of endotoxin, such as lipopolysaccharide (LPS) as a model of sickness behavior, has attracted recent attention. To objectively investigate sickness behavior along with its pain-like behaviors in LPS-treated mice, the behavioral measurement requires accurate methods, which reflects clinical relevance. While reflexive pain response tests have been used for decades for pain assessment, its accuracy and clinical relevance remain problematic. Hence, we used automated home-cage monitoring LABORAS to evaluate spontaneous locomotive behaviors in LPS-induced mice. LPS-treated mice displayed sickness behaviors including pain-like behaviors in automated home-cage monitoring characterized by decreased mobile behaviors (climbing, locomotion, rearing) and increased immobility compared to that of the control group in both short- and long-term locomotive assessments. Here, in short-term measurement, both in the open-field test and automated home-cage monitoring, mice demonstrated impaired locomotive behaviors. We also assessed 24 h long-term locomotor activity in the home-cage system, which profiled the diurnal behaviors of LPS-stimulated mice. The results demonstrated significant behavioral impairment in LPS-stimulated mice compared to the control mice in both light and dark phases. However, the difference is more evident in the dark phase compared to the light phase owing to the nocturnal activity of mice. In addition, the administration of indomethacin as a pharmacological intervention improved sickness behaviors in the open-field test as well as automated home-cage monitoring, confirming that automated home-cage monitoring could be potentially useful in pharmacological screening. Together, our results demonstrate that automated home-cage monitoring could be a feasible alternative to conventional methods, such as the open-field test and combining several behavioral assessments may provide a better understanding of sickness behavior and pain-like behaviors in LPS-treated mice.

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Activation of GPR37 in macrophages confers protection against infection-induced sepsis and pain-like behaviour in mice

Cited by 56 publications

References 58 publications

The Programmed Cell Death of Macrophages, Endothelial Cells, and Tubular Epithelial Cells in Sepsis-AKI

The Programmed Cell Death of Macrophages, Endothelial Cells, and Tubular Epithelial Cells in Sepsis-AKI

Role of Specialized Pro-Resolving Mediators in Neuropathic Pain

Automated home-cage monitoring as a potential measure of sickness behaviors and pain-like behaviors in LPS-treated mice

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