Heme Causes Pain in Sickle Mice <i>via</i> Toll-Like Receptor 4-Mediated Reactive Oxygen Species- and Endoplasmic Reticulum Stress-Induced Glial Activation

Lei, Jianxun; Paul, Jinny; Wang, Ying; Gupta, Mihir; Vang, Derek; Thompson, S.W.N.; Jha, Ritu; Nguyen, Julia; Valverde, Yessenia; Lamarre, Yann; Jones, Michael K.; Gupta, Kalpna

doi:10.1089/ars.2019.7913

Cited by 26 publications

(23 citation statements)

References 65 publications

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“…One limitation of this work is we did not quantitate leukocyte recruitment during VOC physiology; however, we have previously demonstrated reduced leukocyte rolling in Tlr4 -/- mice transplanted with SS BM ( 8 ). Second, our studies have not evaluated SS- Tlr4 -/- mice for reductions in acute pain but recent studies by Lei et al used BERK- SS- Tlr4 -/- mice to demonstrate a causal role of free heme in the genesis of acute and chronic sickle pain ( 12 ).…”

Section: Discussionmentioning

confidence: 99%

“…Specifically, heme, which is released during intravascular hemolysis, is able to serve as a damage-associated molecular pattern (DAMP) to stimulate TLR4 signaling on blood cells and the vasculature leading to vaso-occlusion and pulmonary injury (8)(9)(10)(11). Heme mediates pain via TLR4 in SCD mice and blockade or knockout of TLR4 attenuates hyperalgesia suggesting heme -induced microglial activation via TLR4 in the central nervous system contributes to the initiation and maintenance of sickle pain (12). Consequentially, downstream of TLR4, activation of the pro-inflammatory transcription factor NF-kB leads to the production of cytokines and adhesion molecules that promote inflammation, coagulation, and vaso-occlusion (8,9).…”

Section: Introductionmentioning

confidence: 99%

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Endothelial TLR4 Expression Mediates Vaso-Occlusive Crisis in Sickle Cell Disease

et al. 2021

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Heme, released from red blood cells in sickle cell disease (SCD), interacts with toll-like receptor 4 (TLR4) to activate NF-κB leading to the production of cytokines and adhesion molecules which promote inflammation, pain, and vaso-occlusion. In SCD, TLR4 inhibition has been shown to modulate heme-induced microvascular stasis and lung injury. We sought to delineate the role of endothelial verses hematopoietic TLR4 in SCD by developing a TLR4 null transgenic sickle mouse. We bred a global Tlr4-/- deficiency state into Townes-AA mice expressing normal human adult hemoglobin A and Townes-SS mice expressing sickle hemoglobin S. SS-Tlr4-/- had similar complete blood counts and serum chemistries as SS-Tlr4+/+ mice. However, SS-Tlr4-/- mice developed significantly less microvascular stasis in dorsal skin fold chambers than SS-Tlr4+/+ mice in response to challenges with heme, lipopolysaccharide (LPS), and hypoxia/reoxygenation (H/R). To define a potential mechanism for decreased microvascular stasis in SS-Tlr4-/- mice, we measured pro-inflammatory NF-κB and adhesion molecules in livers post-heme challenge. Compared to heme-challenged SS-Tlr4+/+ livers, SS-Tlr4-/- livers had lower adhesion molecule and cytokine mRNAs, NF-κB phospho-p65, and adhesion molecule protein expression. Furthermore, lung P-selectin and von Willebrand factor immunostaining was reduced. Next, to establish if endothelial or hematopoietic cell TLR4 signaling is critical to vaso-occlusive physiology, we created chimeric mice by transplanting SS-Tlr4-/- or SS-Tlr4+/+ bone marrow into AA-Tlr4-/- or AA-Tlr4+/+ recipients. Hemin-stimulated microvascular stasis was significantly decreased when the recipient was AA-Tlr4-/-. These data demonstrate that endothelial, but not hematopoietic, TLR4 expression is necessary to initiate vaso-occlusive physiology in SS mice.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Endothelial TLR4 Expression Mediates Vaso-Occlusive Crisis in Sickle Cell Disease

et al. 2021

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“…Reactive oxygen species (ROS) are generated by neurons, glia, and immune cells. Many previous studies have shown that ROS are involved in the hyperalgesia in NMDA-induced pain model [ 69 ] or capsaicin-induced pain model [ 70 ] at the spinal cord level, or in visceral pain model [ 71 ] at amygdala level, or in cisplatin-evoked [ 72 ] or CCI -evoked pain model [ 73 ] at DRG level, or in hypoxia/reoxygenation-evoked acute hyperalgesia [ 74 ] at microglia, or in spinal nerve ligation (SNL)-induced NP model at astrocytes [ 75 ]. Moreover, treatment of ROS donor t-BOOH could induce allodynia [ 76 ].…”

Section: Discussionmentioning

confidence: 99%

Targeted up-regulation of Drp1 in dorsal horn attenuates neuropathic pain hypersensitivity by increasing mitochondrial fission

Zhang

et al. 2022

Redox Biology

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Mitochondria play an essential role in pathophysiology of both inflammatory and neuropathic pain (NP), but the mechanisms are not yet clear. Dynamin-related protein 1 (Drp1) is broadly expressed in the central nervous system and plays a role in the induction of mitochondrial fission process. Spared nerve injury (SNI), due to the dysfunction of the neurons within the spinal dorsal horn (SDH), is the most common NP model. We explored the neuroprotective role of Drp1 within SDH in SNI. SNI mice showed pain behavior and anxiety-like behavior, which was associated with elevation of Drp1, as well as increased density of mitochondria in SDH. Ultrastructural analysis showed SNI induced damaged mitochondria into smaller perimeter and area, tending to be circular. Characteristics of vacuole in the mitochondria further showed SNI induced the increased number of vacuole, widened vac-perimeter and vac-area. Stable overexpression of Drp1 via AAV under the control of the Drp1 promoter by intraspinal injection (Drp1 OE) attenuated abnormal gait and alleviated pain hypersensitivity of SNI mice. Mitochondrial ultrastructure analysis showed that the increased density of mitochondria induced by SNI was recovered by Drp1 OE which, however, did not change mitochondrial morphology and vacuole parameters within SDH. Contrary to Drp1 OE, down-regulation of Drp1 in the SDH by AAV-Drp1 shRNA (Drp1 RNAi) did not alter painful behavior induced by SNI. Ultrastructural analysis showed the treatment by combination of SNI and Drp1 RNAi (SNI + Drp1 RNAi) amplified the damages of mitochondria with the decreased distribution density, increased perimeter and area, as well as larger circularity tending to be more circular. Vacuole data showed SNI + Drp1 RNAi increased vacuole density, perimeter and area within the SDH mitochondria. Our results illustrate that mitochondria within the SDH are sensitive to NP, and targeted mitochondrial Drp1 overexpression attenuates pain hypersensitivity. Drp1 offers a novel therapeutic target for pain treatment.

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“…This activation is important for the development and maintenance of neuropathic pain [291]. Interestingly, it was shown that in a mouse model of sickle cell disease, the elevated free heme content in spinal cord tissue due to chronic hemolysis mediates evoked pain hypersensitivity via TLR-mediated activation of microglia [292].…”

Section: The Mφ-iron Liason In the Central Nervous System (Cns)mentioning

confidence: 99%

The Macrophage Iron Signature in Health and Disease

Mertens

Marques

Horvat

et al. 2021

IJMS

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Throughout life, macrophages are located in every tissue of the body, where their main roles are to phagocytose cellular debris and recycle aging red blood cells. In the tissue niche, they promote homeostasis through trophic, regulatory, and repair functions by responding to internal and external stimuli. This in turn polarizes macrophages into a broad spectrum of functional activation states, also reflected in their iron-regulated gene profile. The fast adaptation to the environment in which they are located helps to maintain tissue homeostasis under physiological conditions.

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Heme Causes Pain in Sickle Mice via Toll-Like Receptor 4-Mediated Reactive Oxygen Species- and Endoplasmic Reticulum Stress-Induced Glial Activation

Cited by 26 publications

References 65 publications

Endothelial TLR4 Expression Mediates Vaso-Occlusive Crisis in Sickle Cell Disease

Endothelial TLR4 Expression Mediates Vaso-Occlusive Crisis in Sickle Cell Disease

Targeted up-regulation of Drp1 in dorsal horn attenuates neuropathic pain hypersensitivity by increasing mitochondrial fission

The Macrophage Iron Signature in Health and Disease

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