Sex Differences Revealed in a Mouse CFA Inflammation Model with Macrophage Targeted Nanotheranostics

Liu, Lu; Karagöz, Hüseyi̇n; Herneisey, Michele; Zor, Fatih; Komatsu, Toshimitsu; Loftus, Shannon; Janjic, Bratislav; Gorantla, Vijay S.; Janjić, Jelena M.

doi:10.7150/thno.41309

Cited by 31 publications

(46 citation statements)

References 33 publications

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“…CXB-NE and drug-free nanoemulsion (DF-NE) (vehicle) 5 , 14 , 15 , 25 , 27 treatments were randomized and blinded to investigators. Nanoemulsion was administered on day 8 when the animal is reaching a plateau of pain behavior.…”

Section: Methodsmentioning

confidence: 99%

“…The nanoemulsion pain-relieving therapy selectively targets the COX-2 in macrophages, which is normally produced by these infiltrating cells and other activated cells at the site of injury, triggering pain. 25 The nonsteroidal anti-inflammatory drug (NSAID) CXB can be used to treat pain through the reduction of PGE 2 following selective inhibition of COX-2. We have previously shown that localized delivery of a single micro-dose (0.24 mg/kg) of CXB in nanoemulsion, which is incorporated in circulating macrophages/monocytes that then naturally accumulate at the site of injury provides up to six days of pain relief.…”

Section: Introductionmentioning

confidence: 99%

“…We have previously shown that localized delivery of a single micro-dose (0.24 mg/kg) of CXB in nanoemulsion, which is incorporated in circulating macrophages/monocytes that then naturally accumulate at the site of injury provides up to six days of pain relief. 5 , 14 , 15 , 25 An important feature is that the nanomedicine delivers drug to the affected injured nerve. 5 , 14 , 15 This creates a unique opportunity to assess drug effects on cellular expression of RNAs when the drug is present at the distal injury and virtually no other parts of the peripheral nervous system.…”

Section: Introductionmentioning

confidence: 99%

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Targeted cyclooxygenase-2 inhibiting nanomedicine results in pain-relief and differential expression of the RNA transcriptome in the dorsal root ganglia of injured male rats

et al. 2020

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Chronic constriction injury of the sciatic nerve in rats causes peripheral neuropathy leading to pain-like behaviors commonly seen in humans. Neuropathy is a leading cause of neuropathic pain, which involves a complex cellular and molecular response in the peripheral nervous system with interactions between neurons, glia, and infiltrating immune cells. In this study, we utilize a nonsteroidal anti-inflammatory drug -loaded nanoemulsion to deliver the cyclooxygenase-2 inhibitor, Celecoxib, directly to circulating monocytes following nerve injury, which provides long-lasting pain relief. However, it is not fully understood how cyclooxygenase-2 inhibition in a macrophage traveling to the site of injury impacts gene expression in the dorsal root ganglia. To elucidate aspects of the molecular mechanisms underlying pain-like behavior in chronic constriction injury, as well as subsequent pain relief with treatment, we employ RNAseq transcriptome profiling of the dorsal root ganglia associated with the injured sciatic nerve in rats. Using high throughput RNA sequencing in this way provides insight into the molecular mechanisms involved in this neuroinflammatory response. We compare the transcriptome from the dorsal root ganglias of the following study groups: chronic constriction injury animals administered with cyclooxygenase-2 inhibiting celecoxib-loaded nanoemulsion, chronic constriction injury animals administered with vehicle treatment, a drug-free nanoemulsion, and a group of naïve, unoperated and untreated rats. The results show an extensive differential expression of 115 genes. Using the protein annotation through evolutionary relationship classification system, we have revealed pain-related signaling pathways and underlying biological mechanisms involved in the neuroinflammatory response. Quantitative polymerase chain reaction validation confirms expression changes for several genes. This study shows that by directly inhibiting cyclooxygenase-2 activity in infiltrating macrophages at the injured sciatic nerve, there is an associated change in the transcriptome in the cell bodies of the dorsal root ganglia.

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Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Targeted cyclooxygenase-2 inhibiting nanomedicine results in pain-relief and differential expression of the RNA transcriptome in the dorsal root ganglia of injured male rats

et al. 2020

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“…The NIRF labeled PFC-NEs show an excellent correlation between NIRF signal and 19 F NMR signal in cells and tissues ex vivo [ 35 ]. PFC-NE were also used to image macrophages associated with neuroinflammation in rat nerve injury models [ 27 , 36 – 38 ] and Complete Freund’s Adjuvant (CFA) induced inflammation model in mice [ 28 , 39 ] by in vivo and ex vivo NIRF imaging. In these models, presence of PFC-NE labeled macrophages in target tissues was confirmed using immunohistochemistry and immunofluorescence microscopy [ 27 , 28 , 36 , 38 , 39 ].…”

Section: Introductionmentioning

confidence: 99%

“…PFC-NE were also used to image macrophages associated with neuroinflammation in rat nerve injury models [ 27 , 36 – 38 ] and Complete Freund’s Adjuvant (CFA) induced inflammation model in mice [ 28 , 39 ] by in vivo and ex vivo NIRF imaging. In these models, presence of PFC-NE labeled macrophages in target tissues was confirmed using immunohistochemistry and immunofluorescence microscopy [ 27 , 28 , 36 , 38 , 39 ]. Based on these findings it was conceivable that PFC-NEs with some adaptations could be used to track macrophages in DPN.…”

Section: Introductionmentioning

confidence: 99%

Tracking macrophages in diabetic neuropathy with two-color nanoemulsions for near-infrared fluorescent imaging and microscopy

Nichols

Crelli

Liu

et al. 2021

J Neuroinflammation

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Background The incidence of diabetes and diabetic peripheral neuropathy continues to rise, and studies have shown that macrophages play an important role in their pathogenesis. To date, macrophage tracking has largely been achieved using genetically-encoded fluorescent proteins. Here we present a novel two-color fluorescently labeled perfluorocarbon nanoemulsion (PFC-NE) designed to monitor phagocytic macrophages in diabetic neuropathy in vitro and in vivo using non-invasive near-infrared fluorescent (NIRF) imaging and fluorescence microscopy. Methods Presented PFC-NEs were formulated with perfluorocarbon oil surrounded by hydrocarbon shell carrying two fluorescent dyes and stabilized with non-ionic surfactants. In vitro assessment of nanoemulsions was performed by measuring fluorescent signal stability, colloidal stability, and macrophage uptake and subsequent viability. The two-color PFC-NE was administered to Leprdb/db and wild-type mice by tail vein injection, and in vivo tracking of the nanoemulsion was performed using both NIRF imaging and confocal microscopy to assess its biodistribution within phagocytic macrophages along the peripheral sensory apparatus of the hindlimb. Results In vitro experiments show two-color PFC-NE demonstrated high fluorescent and colloidal stability, and that it was readily incorporated into RAW 264.7 macrophages. In vivo tracking revealed distribution of the two-color nanoemulsion to macrophages within most tissues of Leprdb/db and wild-type mice which persisted for several weeks, however it did not cross the blood brain barrier. Reduced fluorescence was seen in sciatic nerves of both Leprdb/db and wild-type mice, implying that the nanoemulsion may also have difficulty crossing an intact blood nerve barrier. Additionally, distribution of the nanoemulsion in Leprdb/db mice was reduced in several tissues as compared to wild-type mice. This reduction in biodistribution appears to be caused by the increased number of adipose tissue macrophages in Leprdb/db mice. Conclusions The nanoemulsion in this study has the ability to identify phagocytic macrophages in the Leprdb/db model using both NIRF imaging and fluorescence microscopy. Presented nanoemulsions have the potential for carrying lipophilic drugs and/or fluorescent dyes, and target inflammatory macrophages in diabetes. Therefore, we foresee these agents becoming a useful tool in both imaging inflammation and providing potential treatment in diabetic peripheral neuropathy.

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Sustained pain and macrophage infiltration in a mouse muscle contusion model

Cortez,

Gaffney,

Crelli

et al. 2023

Muscle and Nerve

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Introduction/AimsPrior studies have emphasized the role of inflammation in the response to injury and muscle regeneration, but little emphasis has been placed on characterizing the relationship between innate inflammation, pain, and functional impairment. The aim of our study was to determine the contribution of innate immunity to prolonged pain following muscle contusion.MethodsWe developed a closed‐impact mouse model of muscle contusion and a macrophage‐targeted near‐infrared fluorescent nanoemulsion. Closed‐impact contusions were delivered to the lower left limb. Pain sensitivity, gait dysfunction, and inflammation were assessed in the days and weeks post‐contusion. Macrophage accumulation was imaged in vivo by injecting i.v. near‐infrared nanoemulsion.ResultsDespite hindpaw hypersensitivity persisting for several weeks, disruptions to gait and grip strength typically resolved within 10 days of injury. Using non‐invasive imaging and immunohistochemistry, we show that macrophage density peaks in and around the affected muscle 3 day post‐injury and quickly subsides. However, macrophage density in the ipsilateral sciatic nerve and dorsal root ganglia (DRG) increases more gradually and persists for at least 14 days.DiscussionIn this study, we demonstrate pain sensitivity is influenced by the degree of lower muscle contusion, without significant changes to gait and grip strength. This may be due to modulation of pain signaling by macrophage proliferation in the sciatic nerve, upstream from the site of injury. Our work suggests chronic pain developing from muscle contusion is driven by macrophage‐derived neuroinflammation in the peripheral nervous system.

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Sex Differences Revealed in a Mouse CFA Inflammation Model with Macrophage Targeted Nanotheranostics

Cited by 31 publications

References 33 publications

Targeted cyclooxygenase-2 inhibiting nanomedicine results in pain-relief and differential expression of the RNA transcriptome in the dorsal root ganglia of injured male rats

Targeted cyclooxygenase-2 inhibiting nanomedicine results in pain-relief and differential expression of the RNA transcriptome in the dorsal root ganglia of injured male rats

Tracking macrophages in diabetic neuropathy with two-color nanoemulsions for near-infrared fluorescent imaging and microscopy

Sustained pain and macrophage infiltration in a mouse muscle contusion model

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