Chronic pain and impaired glial glutamate transporter function in lupus‐prone mice are ameliorated by blocking macrophage colony‐stimulating factor‐1 receptors

Yan, Xisheng; Maixner, Dylan W.; Fen, LI; Weng, Han‐Rong

doi:10.1111/jnc.13952

Cited by 21 publications

(39 citation statements)

References 76 publications

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“…Finally, we assessed whether immunological changes observed in the brain of FcγRIIB −/− Yaa mice were related to behavioral changes. We conducted the forced swim test and the tail-flick test, which examine depressive-like behavior and heat hyperalgesia, respectively, both of which were shown to be increased in lupus models [32] [33]. FcγRIIB −/− Yaa mice had an increased immobility time and shortened tail-flick latency compared with controls (Fig.…”

Section: Resultsmentioning

confidence: 99%

Unique primed status of microglia under the systemic autoimmune condition of lupus-prone mice

et al. 2019

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BackgroundSystemic lupus erythematosus (SLE) is an autoimmune disease characterized by the production of various autoantibodies. This disease causes disabling neuropsychiatric symptoms even in the absence of apparent inflammation in the central nervous system (CNS), but the mechanisms involved remain unknown. Innate immune-mediated inflammation has attracted attention as a pathogenic mechanism in neuropsychiatric diseases.MethodsWe investigated the CNS of lupus-prone mice focusing on innate immunity. Three strains of lupus-prone mice, FcγRIIB−/−Yaa, an F1 hybrid of NZB and NZW (NZB/NZW) mice, and MRL/Faslpr (MRL/lpr) mice were used to analyze CNS immunopathology.ResultsFlow cytometry analysis demonstrated the numbers of brain CD45+ cells were increased compared with controls in lupus-prone mice. Upregulation of MHC class I and PDCA1 was observed in microglia and CD11b+ myeloid cells of lupus-prone mice, indicating they were activated in response to interferons (IFN). Microglial gene expression analysis of FcγRIIB−/−Yaa mice revealed the upregulation of IFN-responsive genes and inflammation-related genes including Axl, Clec7a, and Itgax, which were previously reported in neurodegenerative conditions and primed conditions. Upregulated chemokine gene expressions including Ccl5 and Cxcl10 were concurrent with increased numbers of T cells and monocytes, especially Ly6Clo monocytes in the CNS. Upregulation of Axl, Clec7a, Itgax, Ccl5, and Cxcl10 was also observed in NZB/NZW mice, indicating common lupus pathology. The primed status of microglia in FcγRIIB−/−Yaa mice was also demonstrated by morphological changes such as enlarged cell bodies with hypertrophic processes, and hyperreactivity to lipopolysaccharide. Immunohistochemistry of FcγRIIB−/−Yaa mice indicated reactive responses of astrocytes and vascular endothelium. Behavioral studies of FcγRIIB−/−Yaa mice revealed depressive-like behavior and heat hyperalgesia in the forced swim test and the tail-flick test, respectively.ConclusionsOur data indicated that microglia in lupus exhibit a unique primed phenotype characterized by the upregulated expressions of neurodegeneration-related genes and IFN-responsive genes. Interaction with peripheral cells and brain resident cells was presumed to orchestrate neuroinflammation. Targeting innate immune cells, such as microglia and monocytes, may be a promising therapeutic approach for neuropsychiatric SLE.

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Section: Resultsmentioning

confidence: 99%

Unique primed status of microglia under the systemic autoimmune condition of lupus-prone mice

et al. 2019

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“…The effect of neutralizing CSF‐1 was detected by Western blot with anti‐CSF‐1 antibody (1:500, R&D, Catalog# AF416). Inhibition of the tyrosine kinase activity of CSF‐1R was achieved by the administration of GW2580 (Millipore Sigma, Burlington, MA, USA, Catalog#344036), as previously described (Conway et al, ; Yan, Maixner, Li, & Weng, ). GW2580 (200 μM in 5 μL ACSF) was injected 2 h before KA injection and 8 hr after KA injection and once per day for an additional three consecutive days through a guide cannula placed in the lateral ventricles and comparing to vehicle control mice.…”

Section: Methodsmentioning

confidence: 99%

“…For loss of function experiments, CSF-1 neutralized antibody (200 ng in 5 μL ACSF, R&D, Minneapolis, MN, USA, Catalog# AF416) or an isotype control antibody (Rat IgG) were injected into ventricles 2 hr before KA injection and 2 hr after KA injection and twice per day, for additional three consecutive days through a guide cannula (from the bregma: MA, USA, Catalog#344036), as previously described (Conway et al, 2005;Yan, Maixner, Li, & Weng, 2017). GW2580 (200 μM in 5 μL ACSF) was injected 2 h before KA injection and 8 hr after KA injection and once per day for an additional three consecutive days through a guide cannula placed in the lateral ventricles and comparing to vehicle control mice.…”

Section: Loss Of Activity Of Csf-1mentioning

confidence: 99%

Microglial proliferation and monocyte infiltration contribute to microgliosis following status epilepticus

Feng

Murugan

Bosco

et al. 2019

Glia

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Microglial activation has been recognized as a major contributor to inflammation of the epileptic brain. Seizures are commonly accompanied by remarkable microgliosis and loss of neurons. In this study, we utilize the CX3CR1GFP/+ CCR2RFP/+ genetic mouse model, in which CX3CR1+ resident microglia and CCR2+ monocytes are labeled with GFP and RFP, respectively. Using a combination of time‐lapse two‐photon imaging and whole‐cell patch clamp recording, we determined the distinct morphological, dynamic, and electrophysiological characteristics of infiltrated monocytes and resident microglia, and the evolution of their behavior at different time points following kainic acid‐induced seizures. Seizure activated microglia presented enlarged somas with less ramified processes, whereas, infiltrated monocytes were smaller, highly motile cells that lacked processes. Moreover, resident microglia, but not infiltrated monocytes, proliferate locally in the hippocampus after seizure. Microglial proliferation was dependent on the colony‐stimulating factor 1 receptor (CSF‐1R) pathway. Pharmacological inhibition of CSF‐1R reduced seizure‐induced microglial proliferation, which correlated with attenuation of neuronal death without altering acute seizure behaviors. Taken together, we demonstrated that proliferation of activated resident microglia contributes to neuronal death in the hippocampus via CSF‐1R after status epilepticus, providing potential therapeutic targets for neuroprotection in epilepsy.

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“…In disease models of pain, macrophages play a key role. For example, in an osteoarthritis model, C-C motif chemokine receptor 2 (Ccr2) signaling, a key driver of macrophage recruitment, is required for movement-provoked pain behaviors (19), and in mice prone to lupus (systemic lupus erythematosus), blocking macrophage colony stimulating factor (m-csf; a factor critical for macrophage recruitment and survival) can attenuate thermal hyperalgesia (20). In rats with diabetic neuropathy, macrophages have also been implicated in eliciting a pain response; depletion of macrophages after traumatic or metabolic nerve injury significantly reduces or prevents the progression of mechanical hyperalgesia and allodynia (21).…”

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confidence: 99%

Macrophage‐derived insulin‐like growth factor‐1 is a key neurotrophic and nerve‐sensitizing factor in pain associated with endometriosis

et al. 2019

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Endometriosis is a common incurable inflammatory disorder that is associated with debilitating pelvic pain in women. Macrophages are central to the pathophysiology of endometriosis: they dictate the growth and vascularization of endometriosis lesions and more recently have been shown to promote lesion innervation. The aim of this study was to determine the mechanistic role of macrophages in producing pain associated with endometriosis. Herein, we show that macrophage depletion in a mouse model of endometriosis can reverse abnormal changes in pain behavior. We identified that disease‐modified macrophages exhibit increased expression of IGF‐1 in an in vitro model of endometriosis‐associated macrophages and confirmed expression by lesion‐resident macrophages in mice and women. Concentrations of IGF‐1 were elevated in peritoneal fluid from women with endometriosis and positively correlate with their pain scores. Mechanistically, we demonstrate that macrophage‐derived IGF‐1 promotes sprouting neurogenesis and nerve sensitization in vitro. Finally, we show that the Igf‐1 receptor inhibitor linsitinib reverses the pain behavior observed in mice with endometriosis. Our data support a role for macrophage‐derived IGF‐1 as a key neurotrophic and sensitizing factor in endometriosis, and we propose that therapies that modify macrophage phenotype may be attractive therapeutic options for the treatment of women with endometriosis‐associated pain.—Forster, R., Sarginson, A., Velichkova, A., Hogg, C., Doming, A., Home, A. W., Saunders, P. T. K., Greaves, E. Macrophage‐derived insulin‐like growth factor‐1 is a key neurotrophic and nerve‐sensitizing factor in pain associated with endometriosis. FASEB J. 33, 11210–11222 (2019). http://www.fasebj.org

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Chronic pain and impaired glial glutamate transporter function in lupus‐prone mice are ameliorated by blocking macrophage colony‐stimulating factor‐1 receptors

Cited by 21 publications

References 76 publications

Unique primed status of microglia under the systemic autoimmune condition of lupus-prone mice

Unique primed status of microglia under the systemic autoimmune condition of lupus-prone mice

Microglial proliferation and monocyte infiltration contribute to microgliosis following status epilepticus

Macrophage‐derived insulin‐like growth factor‐1 is a key neurotrophic and nerve‐sensitizing factor in pain associated with endometriosis

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