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

Abstract

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.

Mass Cytometry of CSF Identifies an MS-Associated B-cell Population

“…Both are ligands of CXCR2, which is involved in the differentiation and migration of oligodendrocyte precursors, and whose disruption enhances remyelination in a mouse model. 32 This interpretation has the encouraging implication that it should be possible to target this neural plasticity therapeutically, independently from immunomodulatory treatments.…”

Co-culture of Schwann cells and endothelial cells for synergistically regulating dorsal root ganglion behavior on chitosan-based anisotropic topology for peripheral nerve regeneration

“…Therefore, the co-culture of SCs and ECs led to an obvious growth of DRG axons. In addition, NGF also has a certain promoting effect on the growth and proliferation of SCs, which may further accelerate the growth and repair of nerves [ 48 ].…”

CXCR2 Signaling and Remyelination in Preclinical Models of Demyelination

“…Strategies to stimulate the maturation of OPCs to myelinating oligodendrocytes are ongoing yet successful translation to effective and sustained therapies has yet to occur. Research from our laboratory and others has shown CXCR2 signaling on oligodendroglia impacts remyelination potentially by augmenting OPC maturation (Liu et al, 2015b;Marro et al, 2019). OPC differentiation into mature myelinating oligodendrocytes is a complex process that is regulated by activation and repression of specific growth and transcription factors as well as epigenetic factors (Tauheed et al, 2016;Santos et al, 2018;Tiane et al, 2019).…”

“…We recently employed a similar approach by generating Plp-Cre-ER(T); Cxcr2 fl/f transgenic mice (Cxcr2-CKO mice) in which Cxcr2 was conditionally ablated upon tamoxifen treatment in adult mice (Marro et al, 2019) (Fig. 1, Fig.…”