Translocator protein is a marker of activated microglia in rodent models but not human neurodegenerative diseases.

Microglial activation plays central roles in neuroinflammatory and neurodegenerative diseases. Positron emission tomography (PET) targeting 18 kDa Translocator Protein (TSPO) is widely used for localising inflammation in vivo, but its quantitative interpretation remains uncertain. We show that TSPO expression increases in activated microglia in mouse brain disease models but does not change in a non-human primate disease model or in common neurodegenerative and neuroinflammatory human diseases. We describe genetic divergence in the TSPO gene promoter, consistent with the hypothesis that the increase in TSPO expression in activated myeloid cells depends on the transcription factor AP1 and is unique to a subset of rodent species within the Muroidea superfamily. Finally, we identify LCP2 and TFEC as potential markers of microglial activation in humans. These data emphasise that TSPO expression in human myeloid cells is related to different phenomena than in mice, and that TSPO-PET signals in humans reflect the density of inflammatory cells rather than activation state.

Does the use of the Bruton Tyrosine Kinase inhibitors and the c-kit inhibitor masitinib result in clinically significant outcomes among patients with various forms of multiple sclerosis?

Multiple sclerosis (MS) is an immune-mediated demyelinating disease of the central nervous system accompanied by chronic inflammation, axonal loss, and neurodegeneration. Traditionally, MS has been thought of as a T-cell mediated disease, but research over the past decade has demonstrated the importance of B cells in both acute demyelination and disease progression. The highly selective irreversible Bruton Tyrosine Kinase (BTK) inhibitors evobrutinib, tolebrutinib, and orelabrutinib, and the reversible BTK inhibitor fenebrutinib, all target B-cell activation and aspects of innate immunity, including macrophage and microglia biology. The c-KIT inhibitor masitinib mitigates neuroinflammation by controlling the survival, migration, and degranulation of mast cells, leading to the inhibition of proinflammatory and vasoactive molecular cascades that result from mast cell activation. This article will review and critically appraise the ongoing clinical trials of two classes of receptor tyrosine kinase inhibitors that are emerging as potential medical treatments for the varying subtypes of MS: BTK inhibitors and c-KIT inhibitors. Specifically, this review will attempt to answer whether BTK inhibitors have measurable positive clinical effects on patients with RRMS, SPMS with relapses, relapse-free SPMS, and PPMS through their effect on MRI T1 lesions; annualized relapse rate; EDSS scale; MSFC score; and time to onset of composite 12-week confirmed disability progression. Additionally, this review will examine the literature to determine if masitinib has positive clinical effects on patients with PPMS or relapse-free SPMS through its effect on EDSS or MSFC scores.

Investigating the NLRP3 inflammasome and its regulator miR-223-3p in multiple sclerosis and experimental demyelination.

Innate immune signaling pathways are essential mediators of inflammation and repair following myelin injury. Inflammasome activation has recently been implicated as a driver of myelin injury in multiple sclerosis (MS) and its animal models, although the regulation and contributions of inflammasome activation in the demyelinated central nervous system (CNS) are not completely understood. Herein, we investigated the NLRP3 (NBD-, LRR- and pyrin domain-containing protein 3) inflammasome and its endogenous regulator microRNA-223-3p within the demyelinated CNS in both MS and an animal model of focal demyelination. We observed that NLRP3 inflammasome components and microRNA-223-3p were upregulated at sites of myelin injury within activated macrophages and microglia. Both microRNA-223-3p and a small-molecule NLRP3 inhibitor, MCC950, suppressed inflammasome activation in macrophages and microglia in vitro; compared with microglia, macrophages were more prone to inflammasome activation in vitro. Finally, systemic delivery of MCC950 to mice following lysolecithin-induced demyelination resulted in a significant reduction in axonal injury within demyelinated lesions. In conclusion, we demonstrate that NLRP3 inflammasome activity by macrophages and microglia is a critical component of the inflammatory microenvironment following demyelination and represents a potential therapeutic target for inflammatory-mediated demyelinating diseases, including MS. Cover Image for this issue: https://doi.org/10.1111/jnc.15422.