Spatiotemporal ablation of CXCR2 on oligodendrocyte lineage cells

Liu, Liping; Spangler, Lisa C.; Prager, Briana C.; Benson, Bryan L.; Hu, Bingqing; Shi, Samuel; Love, Anna; Zhang, Cunjin; Yu, Meigen; Cotleur, Anne C.; Ransohoff, Richard M.

doi:10.1212/nxi.0000000000000174

Cited by 8 publications

(15 citation statements)

References 13 publications

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“…Previously, members of our group (25) generated mice in which Cxcr2 was selectively ablated in oligodendrocytes. Similar to the findings for the animals that we report here, Cxcr2 was silenced within oligodendroglia in adult mice upon tamoxifen treatment (25). Employing toxin models of demyelination, the authors clearly showed enhanced remyelination in animals in which CXCR2 signaling in oligodendrocytes was inhibited, arguing for an important role for this chemokine receptor in influencing oligodendrocyte biology.…”

Section: Discussionsupporting

confidence: 86%

“…Through EM analysis of the spinal cords of the experimental mice, we determined that an increase in the remyelination of axons occurred following targeting of CXCR2 and that this correlated with an increased myelin thickness compared to that in control animals. Collectively, these findings support the concept that targeted ablation of CXCR2 on oligodendroglia in adult mice may enhance the maturation of OPCs into myelin-producing oligodendrocytes (25,58).…”

Section: Discussionsupporting

confidence: 77%

“…Cxcr2-CKO mice were treated twice daily with either 1 mg tamoxifen or vehicle, followed by resting for 2 weeks, at which point the spinal cords were removed to evaluate spinal cord myelin. Similar to the findings of Liu et al (25), we did not detect any differences in either the size or behavior in tamoxifen-treated Cxcr2-CKO mice compared to their vehicle-treated littermates. Assessment of spinal cord myelin via toluidine blue staining revealed no overt differences between tamoxifen-treated Cxcr2-CKO mice and vehicle-treated control Cxcr2-CKO mice ( Fig.…”

supporting

confidence: 91%

“…In addition to being expressed on circulating myeloid cells, CXCR2 is also expressed on neurons (45,46), cerebral endothelial cells (60,61), as well as resident glia, including microglia (45,47) and oligodendrocytes (13,14,22,25,62,63). Further, addition of IFN-␥ to cultured OPCs derived from mouse neural progenitor cells results in apoptosis, while inclusion of the CXCL1 protein blocks OPC apoptotic death (14).…”

Section: Discussionmentioning

confidence: 99%

“…Remyelination is enhanced upon silencing of CXCR2 in oligodendroglia. Previous work has indicated that targeting of CXCR2 signaling through either administration of receptor-specific small molecules (58) or genetic targeting (25) results in increased remyelination. To determine whether remyelination was occurring following tamoxifen-mediated silencing of Cxcr2 signaling, JHMV-infected Cxcr2-CKO mice were sacrificed at day 28 p.i., and EM analysis of spinal cord sections was performed to calculate g ratios.…”

mentioning

confidence: 99%

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Disrupted CXCR2 Signaling in Oligodendroglia Lineage Cells Enhances Myelin Repair in a Viral Model of Multiple Sclerosis

Marro

Skinner

Cheng

et al. 2019

J Virol

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CXCR2 is a chemokine receptor expressed on oligodendroglia that has been implicated in the pathogenesis of neuroinflammatory demyelinating diseases as well as enhancement of the migration, proliferation, and myelin production by oligodendroglia. Using an inducible proteolipid protein (Plp) promoter-driven Cre-loxP recombination system, we were able to assess how timed ablation of Cxcr2 in oligodendroglia affected disease following intracranial infection with the neurotropic JHM strain of mouse hepatitis virus (JHMV). Generation of Plp-Cre-ER(T)::Cxcr2 flox/flox transgenic mice (termed Cxcr2-CKO mice) allows for Cxcr2 to be silenced in oligodendrocytes in adult mice following treatment with tamoxifen. Ablation of oligodendroglia Cxcr2 did not influence clinical severity in response to intracranial infection with JHMV. Infiltration of activated T cells or myeloid cells into the central nervous system (CNS) was not affected, nor was the ability to control viral infection. In addition, the severity of demyelination was similar between tamoxifen-treated mice and vehicletreated controls. Notably, deletion of Cxcr2 resulted in increased remyelination, as assessed by g-ratio (the ratio of the inner axonal diameter to the total outer fiber diameter) calculation, compared to that in vehicle-treated control mice. Collectively, our findings argue that CXCR2 signaling in oligodendroglia is dispensable with regard to contributing to neuroinflammation, but its deletion enhances remyelination in a preclinical model of the human demyelinating disease multiple sclerosis (MS). IMPORTANCE Signaling through the chemokine receptor CXCR2 in oligodendroglia is important for developmental myelination in rodents, while chemical inhibition or nonspecific genetic deletion of CXCR2 appears to augment myelin repair in animal models of the human demyelinating disease multiple sclerosis (MS). To better understand the biology of CXCR2 signaling on oligodendroglia, we generated transgenic mice in which Cxcr2 is selectively ablated in oligodendroglia upon treatment with tamoxifen. Using a viral model of neuroinflammation and demyelination, we demonstrate that genetic silencing of CXCR2 on oligodendroglia did not affect clinical disease, neuroinflammation, or demyelination, yet there was increased remyelination. These findings support and extend previous findings suggesting that targeting CXCR2 may offer a therapeutic avenue for enhancing remyelination in patients with demyelinating diseases.

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Section: Discussionsupporting

confidence: 86%

Section: Discussionsupporting

confidence: 77%

supporting

confidence: 91%