Biology subjects

Zierler, S.

Publications and source records attributed to Zierler, S..

4 recordsLinked to original sources

bioRxiv2026

Pathogenicity of autoreactive TH17 cells is modulated by the TRPM7 kinase

The melastatin-like transient receptor potential channel, TRPM7, is crucial for signaling in leukocytes. It harbors a channel domain, permeable to divalent cations as well as a serine/threonine -kinase, phosphorylating inter alia SMAD2. TRPM7 kinase activity is essential for the differentiation of non-pathogenic T helper 17 (TH17) cells as well as for T cell colonization and alloreactivity in the gut. As pathogenic TH17 (pTH17) cells drive autoimmune diseases, we studied TRPM7 kinase involvement in pTH17 polarization and function as well as in the development of multiple sclerosis (MS), using human T cells and established murine experimental autoimmune encephalomyelitis (EAE) models. Our results reveal an elevated TRPM7 activity in T effector cells derived from the cerebrospinal fluid (CSF) of MS patients, in line with higher functional TRPM7 expression on human TH17 cells. Utilizing a mouse line with disrupted kinase activity (Trpm7R/R), we uncovered both impaired differentiation of pathogenic TH17 cells as well as a significantly milder course of TH17-mediated transfer EAE in Trpm7R/R mice compared to Trpm7+/+ controls. In the CNS of Trpm7R/R mice, the number of FOXP3+ T cells (Tregs) was increased, while fewer TH17 cells infiltrated the CNS due to a migration defect of transferred pTH17 cells in the Trpm7R/R hosts and a failure to reactivate in the intestine, due to reduced MHCII signaling. Thus, inactivation of TRPM7 kinase may represent a promising therapeutic strategy targeting both differentiation and reactivation of pTH17 cells while preserving Tregs function and thereby dampening CNS inflammation in MS.

immunology↗

bioRxiv2026

Preimplantation factor (PIF) is an endogenous inhibitor of potassium channel KV1.3 regulating neutrophil function during pregnancy

Pregnancy is a unique period regarding immune cell regulation. Within the placenta, maternal immune cells play a central role in immune surveillance and tissue remodeling. However, regulatory mechanisms of systemic immunity during pregnancy are less clear. Here, we show that neutrophil function is altered in pregnant mice (E13.5), indicated by increased slow rolling velocity and reduced adhesion. Mechanistically, PreImplantation factor (PIF), a 15 amino acid peptide which is produced by human and murine trophoblast cells of the placenta, is continuously secreted into the maternal circulation and plays a key role in modulating neutrophil function via blocking the voltage-gated potassium channel KV1.3. This resulted in impaired intracellular Ca2+ signaling and subsequently disturbance of neutrophil post-arrest modifications and a higher susceptibility to physiological shear forces in vivo and in vitro. Furthermore, PIF-mediated KV1.3 blockade impaired E-selectin-mediated release of S100A8/A9 and phagocytosis. Taken together, we have identified PIF as an important modulator of neutrophil function during pregnancy suggesting a critical role in regulating innate immune responses throughout gestation.

immunology↗

bioRxiv2024

TRPM7 activity drives human CD4 T-cell activation and differentiation in a magnesium dependent manner

T lymphocyte activation is a crucial process in the regulation of innate and adaptive immune responses. The ion channel-kinase TRPM7 has previously been implicated in cellular Mg2+ homeostasis, proliferation, and immune cell modulation. Here, we show that pharmacological and genetic silencing of TRPM7 leads to diminished human CD4 T-cell activation and proliferation following TCR mediated stimulation. In both primary human CD4 T cells and CRISPR/Cas-9 engineered Jurkat T cells, loss of TRPM7 led to altered Mg2+ homeostasis, Ca2+ signaling, reduced NFAT translocation, decreased IL-2 secretion and ultimately diminished proliferation and differentiation. While the activation of primary human CD4 T cells was dependent on TRPM7, polarization of naive CD4 T cells into regulatory T cells (Treg) was not. Taken together, these results highlight TRPM7 as a key protein of cellular Mg2+ homeostasis and CD4 T-cell activation. Its role in lymphocyte activation suggests therapeutic potential for TRPM7 in numerous T-cell mediated diseases. SummaryTRPM7 is crucial to maintaining cellular Mg2+ homeostasis and regulates human CD4 T-cell activation by modulating early Ca2+ signaling events in response to TCR-mediated stimulation subsequently, influencing T-cell differentiation in a Mg2+ dependent manner.

immunology↗

bioRxiv2022

Macrophages and glia are the dominant P2X7-expressing cell types in the gut nervous system - no evidence for a role of neuronal P2X7 receptors in colitis

SummaryBlockade or deletion of the pro-inflammatory P2X7 receptor channel has been shown to reduce tissue damage and symptoms in models of inflammatory bowel disease (IBD) and P2X7 receptors on enteric neurons were suggested to mediate neuronal death and associated motility changes. Here we used P2X7-specific antibodies and nanobodies as well as a BAC transgenic P2X7-EGFP reporter mouse model and P2rx7-/- controls to perform a detailed analysis of cell type-specific P2X7 expression and possible overexpression effects in the enteric nervous system. In contrast to previous studies, we did not detect P2X7 in neurons but found dominant expression in glia and macrophages which closely interact with the neurons. P2X7 overexpression per se did not induce significant pathological effects. Our data indicate that macrophages and/or glia account for P2X7-mediated neuronal damage in IBD and provide a refined basis for the exploration of P2X7-based therapeutic strategies.

physiology↗