Macrophage angiotensin II type 2 receptor triggers neuropathic pain

Shepherd, Andrew J.; Mickle, Aaron D.; Golden, Judith P.; Mack, Madison R.; Halabi, Carmen M.; Kloet, Annette D. de; Samineni, Vijay K.; Kim, Brian; Krause, Eric G.; Gereau, Robert W.; Mohapatra, Durga P.

doi:10.1073/pnas.1721815115

Cited by 109 publications

(125 citation statements)

References 69 publications

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“…A recent report 21 took a different approach, using the macrophage Fas-induced apoptosis (MAFIA) transgenic mouse line 22 . As for the TK or DTR mice, this line expresses a suicide gene (Fas) under the control of the CSF1R promoter, which is specifically expressed in macrophages and microglia.…”

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confidence: 99%

“…Importantly, as this transgenic line coexpresses green fluorescent protein (GFP) under control of the same promoter, it is possible to monitor the distribution of cells that express the suicide gene and the extent of their depletion. Using the MAFIA mice, Shepherd et al 21 demonstrated reduced nerve injury-induced mechanical hypersensitivity, a hallmark of the neuropathic pain phenotype, after depletion of circulating monocytes and macrophages at the nerve injury site. Moreover, as these authors found that DRG macrophages were spared, they concluded that peripheral macrophages, but not those in the DRG, are the critical contributors to nerve injury-induced neuropathic pain 21 .…”

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confidence: 99%

“…Using the MAFIA mice, Shepherd et al 21 demonstrated reduced nerve injury-induced mechanical hypersensitivity, a hallmark of the neuropathic pain phenotype, after depletion of circulating monocytes and macrophages at the nerve injury site. Moreover, as these authors found that DRG macrophages were spared, they concluded that peripheral macrophages, but not those in the DRG, are the critical contributors to nerve injury-induced neuropathic pain 21 . However, their conclusion was not consistent with an earlier study reporting that selective depletion of peripheral monocytes/macrophages, while sparing DRG macrophages, had limited impact on neuropathic pain development 6 .…”

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Dorsal root ganglion macrophages contribute to both the initiation and persistence of neuropathic pain

et al. 2020

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Paralleling the activation of dorsal horn microglia after peripheral nerve injury is a significant expansion and proliferation of macrophages around injured sensory neurons in dorsal root ganglia (DRG). Here we demonstrate a critical contribution of DRG macrophages, but not those at the nerve injury site, to both the initiation and maintenance of the mechanical hypersensitivity that characterizes the neuropathic pain phenotype. In contrast to the reported sexual dimorphism in the microglial contribution to neuropathic pain, depletion of DRG macrophages reduces nerve injury-induced mechanical hypersensitivity and expansion of DRG macrophages in both male and female mice. However, fewer macrophages are induced in the female mice and deletion of colony-stimulating factor 1 from sensory neurons, which prevents nerve injury-induced microglial activation and proliferation, only reduces macrophage expansion in male mice. Finally, we demonstrate molecular cross-talk between axotomized sensory neurons and macrophages, revealing potential peripheral DRG targets for neuropathic pain management.

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Dorsal root ganglion macrophages contribute to both the initiation and persistence of neuropathic pain

et al. 2020

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“…administration of Ang II causes hypersensitivity (Shepherd, Copits, et al, ). While it was suggested that the induction of neuropathic pain involves the activation of AT2 receptors in DRGs (Smith et al, ), other reports indicate that it involves AT2 receptors on peripheral macrophages (Shepherd, Copits, et al, ; Shepherd, Mickle, et al, ). As the action site of Ang II is still debated and requires further studies, we have investigated pain transmission from the perspective of the spinal Ang system.…”

Section: Resultsmentioning

confidence: 99%

Anti‐hypersensitive effect of angiotensin (1‐7) on streptozotocin‐induced diabetic neuropathic pain in mice

Okita

Nemoto

Yamagata

et al. 2018

European Journal of Pain

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Background We have recently reported that the spinal angiotensin (Ang) converting enzyme (ACE)/Ang II/AT1 receptor axis and downstream p38 MAPK phosphorylation are activated in streptozotocin (STZ)‐induced diabetic mice and lead to tactile hypersensitivity. Moreover, our previous results suggested that the intrathecal (i.t.) administration of Ang (1‐7), an N‐terminal fragment of Ang II, may attenuate the Ang II‐induced nociceptive behaviour through the inhibition of p38 MAPK phosphorylation via Mas receptors. Here, we investigated whether the i.t. administration of Ang (1‐7) can attenuate STZ‐induced diabetic neuropathic pain. Methods Tactile and thermal hypersensitivities were determined using the von Frey filament and Hargreaves tests, respectively. The protein expression of ACE2, Mas receptors and phospho‐p38 MAPK was measured by western blotting. Spinal ACE2 activity was determined using ACE2 activity assay kit. Results The i.t. administration of Ang (1‐7) significantly reduced the tactile and thermal hypersensitivities on day 14 after STZ injection, and these effects were significantly prevented by the Mas receptor antagonist A779. The expression of ACE2 and Mas receptors in the plasma membrane fraction of the lumbar dorsal spinal cord was both significantly decreased in STZ mice. Spinal ACE2 activity was also decreased while p38 MAPK phosphorylation was increased in the lumbar dorsal region of these mice. This phosphorylation was attenuated by the injection of Ang (1‐7), whose effect was reversed by A779. Conclusions Our data demonstrate that Ang (1‐7) attenuates STZ‐induced diabetic neuropathic pain and that this occurs through a mechanism involving spinal Mas receptors and he inhibition of p38 MAPK phosphorylation. Significance The ACE2/Ang (1‐7)/Mas receptor axis was down‐regulated in the spinal cord of STZ mice and the i.t. administration of Ang (1‐7) attenuated the STZ‐induced diabetic neuropathic pain via Mas receptors. Therefore, the activation of this axis could be an effective therapeutic target to alleviate the neuropathic pain in diabetic patients.

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“…Though it has the capacity to regenerate, the PNS is also prone to injury and degeneration (8). Studies of PNS injury have shown that PNS macrophages play important roles for debris clearance, pain development, and regeneration (9, 10, 11). While the contribution of recruited monocytes cannot be excluded, these studies demonstrate the importance of PNS macrophages in nerve injury.…”

Section: Introductionmentioning

confidence: 99%

Peripheral nerve resident macrophages are microglia-like cells with tissue-specific programming

Wang

Yim

Avey

et al. 2019

Preprint

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Whereas microglia are recognized as fundamental players in central nervous system 16 (CNS) development and function, much less is known about macrophages of the peripheral nervous 17 system (PNS). Here we show that self-maintaining PNS macrophages share unique features with 18 CNS microglia. By comparing gene expression across neural and conventional tissue-resident 19 macrophages, we identified transcripts that were shared among neural resident macrophages as 20 well as selectively enriched in PNS macrophages. Remarkably, PNS macrophages constitutively 21 expressed genes previously identified to be upregulated by activated microglia during aging or 22 neurodegeneration. Several microglial activation-associated and PNS macrophage-enriched genes 23 were also expressed in spinal cord microglia at steady state. While PNS macrophages arose from 24 both embryonic and hematopoietic precursors, their expression of activation-associated genes did 25 not differ by ontogeny. Collectively, these data uncover shared and unique features between neural 26 resident macrophages and emphasize the role of nerve environment for shaping PNS macrophage 27 identity. 283 Introduction: The significant role of resident neural macrophages in neuroinflammation and disease 29 progression is increasingly appreciated in mouse models and individuals with neurodegeneration (1, 30 2, 3). Such advances, which largely rely on the interpretation of data from transcriptional analyses 31 and human genome-wide association studies (GWAS) of Alzheimer's Disease (AD) and other 32 neurodegenerative conditions, have led to critical findings about cellular and molecular processes 33 underlying such diseases (4, 5, 6). Most of these studies, however, have focused on resident 34 macrophages in the brain (microglia) and, to a lesser extent, the spinal cord. Meanwhile, the 35 transcriptional identity and functions of resident macrophages in the PNS remain mostly unknown. 36The PNS consists of a multitude of neuronal networks that relay motor and sensory 37 information between the CNS and the rest of the body (7). Though it has the capacity to regenerate, 38 the PNS is also prone to injury and degeneration (8). Studies of PNS injury have shown that PNS 39 macrophages play important roles for debris clearance, pain development, and regeneration (9, 10, 40 11). While the contribution of recruited monocytes cannot be excluded, these studies demonstrate 41 the importance of PNS macrophages in nerve injury. Understanding the roles of these cells in 42 homeostasis and disease may be broadly beneficial for resolving neuroinflammation. 43In addition to monocyte-derived macrophages in nerve injury, there are also resident 44 macrophages in the PNS at steady state (12, 13). While their residence in neuronal tissues is 45 inherently microglia-like, PNS macrophages exist within a unique peripheral nerve 46 microenvironment. Moreover, though it is known that CNS microglia are derived from the yolk sac 47 during embryogenesis and depend on IL-34 for development (14, 15), the ...

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Macrophage angiotensin II type 2 receptor triggers neuropathic pain

Cited by 109 publications

References 69 publications

Dorsal root ganglion macrophages contribute to both the initiation and persistence of neuropathic pain

Dorsal root ganglion macrophages contribute to both the initiation and persistence of neuropathic pain

Anti‐hypersensitive effect of angiotensin (1‐7) on streptozotocin‐induced diabetic neuropathic pain in mice

Peripheral nerve resident macrophages are microglia-like cells with tissue-specific programming

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