Biology subjects

Schmitz, I.

Publications and source records attributed to Schmitz, I..

3 recordsLinked to original sources

bioRxiv2025

Modulation of repopulating microglia in multiple sclerosis models with implications for neuroprotection

Microglia play a critical role in central nervous system (CNS) pathologies including multiple sclerosis (MS), and their modulation offers therapeutic potential especially during progressive disease courses. Using cell culture and experimental autoimmune encephalomyelitis (EAE) models, we investigated microglial dynamics during depletion and repopulation (MGrepo) and their modulation using siponimod (sipo), an established CNS penetrating MS medication. Repopulating microglia exhibited a transient reactive state (CD86, MHC-II, Il1b, Tnf). Sipo modulated microglia populations, increasing CD163+, CD206+, and CX3CR1+ while reducing CD86+MHC-II+ cells accompanied by a reduction of neuronal damage. Proteomic spinal cord analysis revealed protein expression alterations by MGrepo and sipo linked to inflammation, myelination, and neuronal structural organization, supported by RNA sequencing of the spinal cord. The neuroinflammation attenuating role of sipo could be linked to cell maintenance and myelin formation associated processes. These findings highlight the capacity of pharmacological interventions to modulate microglia, offering new insights into therapeutic strategies targeting microglial activity in neuroinflammatory diseases.

neuroscience↗

bioRxiv2020

Murine Staphylococcus aureus chronic infection is cured by theory-driven therapy

Staphylococcus aureus is considered a dangerous pathogen due to its ability to evade the immune system and resist multiple antibiotics. These evasive strategies lead to difficult-to-treat chronic infections and abscesses in internal organs including kidneys, which are associated with the expansion of myeloid-derived suppressor cells (MDSCs) and their suppressive effect on T cells. Here, we developed a mathematical model of chronic S. aureus infection that incorporates the T-cell suppression by MDSCs and suggests therapeutic strategies to eradicate S. aureus. We quantified in silico a therapeutic protocol with heat-killed S. aureus (HKSA), which we tested in vivo. Contrary to conventional administration of heat-killed bacteria as vaccination prior to infection, we administered HKSA as treatment, when the hosts were already chronically infected. Our treatment cured all chronically S. aureus-infected mice, reduced MDSCs, and reversed T-cell dysfunction by inducing acute inflammation during ongoing, chronic infection without any use of standard treatments that involve antibiotics, MDSC-targeting drugs (chemotherapy), or procedures such as abscess drainage. This study is a proof-of-principle for a treatment protocol against chronic S. aureus infection and renal abscesses by repurposing heat-killed treatments, guided and quantified by mathematical modelling. Our mathematical model further explains why previous treatment with inactivated S. aureus administered to long-term infected human patients has not led to cure. Overall, our results can have direct relevance to the design of human therapeutics against chronic S. aureus infections. In briefA theory-driven treatment protocol with heat-killed S. aureus eradicates S. aureus, reduces MDSCs, and reverses T-cell dysfunction in vivo. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=157 HEIGHT=200 SRC="FIGDIR/small/910786v3_ufig1.gif" ALT="Figure 1"> View larger version (66K): org.highwire.dtl.DTLVardef@1e2d0c9org.highwire.dtl.DTLVardef@1f97374org.highwire.dtl.DTLVardef@b0235org.highwire.dtl.DTLVardef@bdf2ee_HPS_FORMAT_FIGEXP M_FIG C_FIG

systems biology↗

bioRxiv2018

A hypermorphic Nfkbid allele represents an Idd7 locus gene contributing to impaired thymic deletion of autoreactive diabetogenic CD8+ T-cells in NOD mice.

In both NOD mice and humans, the development of type 1 diabetes (T1D) is dependent in part on autoreactive CD8+ T-cells recognizing pancreatic {beta}-cell peptides presented by often quite common MHC class I variants. Studies in NOD mice previously revealed the common H2-Kd and/or H2-Db class I molecules expressed by this strain acquire an aberrant ability to mediate pathogenic CD8+ T-cell responses through interactions with T1D susceptibility (Idd) genes outside the MHC. A gene(s) mapping to the Idd7 locus on proximal Chromosome 7 was previously shown to be an important contributor to the failure of the common class I molecules expressed by NOD mice to mediate the normal thymic negative selection of diabetogenic CD8+ T-cells. Using an inducible model of thymic negative selection and mRNA transcript analyses we initially identified an elevated Nfkbid expression variant is likely an NOD Idd7 region gene contributing to impaired thymic deletion of diabetogenic CD8+ T-cells. CRISPR/Cas9-mediated genetic attenuation of Nfkbid expression in NOD mice resulted in improved negative selection of autoreactive diabetogenic AI4 and NY8.3 CD8+ T-cells. These results indicated allelic variants of Nfkbid represent an Idd7 gene contributing to the efficiency of intrathymic deletion of diabetogenic CD8+ T-cells. However, while enhancing thymic deletion of pathogenic CD8+ T-cells, ablation of Nfkbid expression surprisingly accelerated T1D onset in NOD mice likely at least in part by numerically decreasing regulatory T- and B-lymphocytes (Tregs/Bregs), thereby reducing their peripheral immunosuppressive effects.

immunology↗