Unexpected additive effects of minocycline and hydroxychloroquine in models of multiple sclerosis: Prospective combination treatment for progressive disease?

Background: Most multiple sclerosis (MS) patients succumb to a progressive phenotype. Continued lymphocyte activity in the brain, microglia-mediated injury, iron deposition, and oxidative stress are characteristics of progressive MS.

Objective: As minocycline and hydroxychloroquine have been shown to inhibit microglia, we evaluated their effects on other outcomes relevant for progression.

Impact of Minocycline on Extracellular Matrix Metalloproteinase Inducer, a Factor Implicated in Multiple Sclerosis Immunopathogenesis.

Extracellular matrix metalloproteinase inducer (EMMPRIN, CD147) is a transmembrane glycoprotein that is upregulated on leukocytes in active lesions in multiple sclerosis (MS) and its animal model, experimental autoimmune encephalomyelitis (EAE). Administration of anti-EMMPRIN Abs reduces the severity of EAE. Minocycline is a tetracycline antibiotic with immune-modulatory properties that decreases the severity of EAE; it was recently found to attenuate the conversion from a first demyelinating event to clinically definite MS in a phase III trial.

Evaluating Soluble EMMPRIN as a Marker of Disease Activity in Multiple Sclerosis: Studies of Serum and Cerebrospinal Fluid.

Extracellular matrix metalloproteinase inducer (EMMPRIN, CD147) is an inducer of matrix metalloproteinases and has roles in leukocyte activation and migration. We reported previously that in MS and its animal model, experimental autoimmune encephalomyelitis, cell surface-associated EMMPRIN was significantly elevated in leukocytes around inflammatory perivascular cuffs in the CNS. In this study we report that activated T-cells can secrete soluble form of EMMPRIN (sEMMPRIN) upon activation.

The role of EMMPRIN in T cell biology and immunological diseases.

EMMPRIN (CD147), originally described as an inducer of the expression of MMPs, has gained attention in its involvement in various immunologic diseases, such that anti-EMMPRIN antibodies are considered as potential therapeutic medications. Given that MMPs are involved in the pathogenesis of various disease states, it is relevant that targeting an upstream inducer would make for an effective therapeutic strategy. Additionally, EMMPRIN is now appreciated to have multiple roles apart from MMP induction, including in cellular functions, such as migration, adhesion, invasion, energy metabolism, as well as T cell activation and proliferation.

EMMPRIN, an upstream regulator of MMPs, in CNS biology.

Matrix metalloproteinases (MMPs) are engaged in pathologies associated with infections, tumors, autoimmune disorders and neurological dysfunctions. With the identification of an upstream regulator of MMPs, EMMPRIN (Extracellular matrix metalloproteinase inducer, CD147), it is relevant to address if EMMPRIN plays a role in the pathology of central nervous system (CNS) diseases. This would enable the possibility of a more upstream and effective therapeutic target.

Substitution for Asn460 cripples β-galactosidase (Escherichia coli) by increasing substrate affinity and decreasing transition state stability.

Substrate initially binds to β-galactosidase (Escherichia coli) at a 'shallow' site. It then moves ∼3Å to a 'deep' site and the transition state forms. Asn460 interacts in both sites, forming a water bridge interaction with the O3 hydroxyl of the galactosyl moiety in the shallow site and a direct H-bond with the O2 hydroxyl of the transition state in the deep site.

Smad4 deficiency in T cells leads to the Th17-associated development of premalignant gastroduodenal lesions in mice.

While there is evidence that specific T cell populations can promote the growth of established tumors, instances where T cell activity causes neoplasms to arise de novo are infrequent. Here, we employed two conditional mutagenesis systems to delete the TGF-β signaling pathway component Smad4 in T cells and observed the spontaneous development of massive polyps within the gastroduodenal regions of mice. The epithelial lesions contained increased levels of transcripts encoding IL-11, IL-6, TGF-β, IL-1β, and TNF-α, and lamina propria cells isolated from lesions contained abundant IL-17A+CD4+ T cells.

Absence of the cellular prion protein exacerbates and prolongs neuroinflammation in experimental autoimmune encephalomyelitis.

Although the physiological roles of the cellular prion protein (PrP C) remain to be fully elucidated, PrP C has been proposed to represent a potential regulator of cellular immunity. To test this hypothesis, we evaluated the consequences of PrP C deficiency on the course of experimental autoimmune encephalomyelitis induced by immunization with myelin oligodendrocyte glycoprotein peptide. Consistent with augmented proliferative responses and increased cytokine gene expression by myelin oligodendrocyte glycoprotein-primed Prnp-/- T cells, PrP C-deficient mice demonstrated more aggressive disease onset and a lack of clinical improvement during the chronic phase of experimental autoimmune encephalomyelitis.

Mgmt deficiency alters the in vivo mutational spectrum of tissues exposed to the tobacco carcinogen 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK).

It has been proposed that O(6)-methylguanine DNA methyltransferase (MGMT) gene silencing in premalignant lesions and cancers of the lung might result in the acquisition of a 'mutator' phenotype. Previously, however, we found that Mgmt(-/-) mouse DNA failed to show an increase in spontaneous mutations. We thus hypothesized that only during exposure to specific environmental carcinogens would the consequences of MGMT deficiency become evident.