Biology subjects

Kozlowska, E.

Publications and source records attributed to Kozlowska, E..

3 recordsLinked to original sources

bioRxiv2025

Dystrophin Dp71 is essential for the development and function of macrophages

Mutations in the DMD gene, encoding dystrophins, cause progressive muscle degeneration with severe sterile inflammation. While macrophages predominate amongst muscle-infiltrating cells, being central to both damage and regeneration, they were not known to express dystrophin. Yet, we recently demonstrated Dp71 dystrophin expression correlating with tumour infiltrating macrophages. Here we report physiological, developmentally regulated expression of Dp71 in human and mouse hematopoietic stem cells, which decreases with cell maturation into bone marrow macrophages (BMM). Proteomics with molecular and functional analyses in mouse dystrophin-null BMM and peritoneal macrophages reveal that absence of dystrophin disturbs their development. Alterations in over 300 proteins mapped to pathways and networks relating to reduced migration and phagocytosis and increased NLRP3 inflammasome functions. These defects are Dp71-dependent and not caused by the dystrophic environment, since Dmdmdx mouse macrophages, which express Dp71, are not affected. Thus, we identify an important new role for the DMD gene. Altered Dp71 expression in tumour microenvironment cells and in dystrophin-null patients should be investigated to understand the commonalities between DMD and tumours, and potentially identify new treatments.

cell biology↗

bioRxiv2024

Huntingtin loss-of-function contributes to transcriptional deregulation in Huntington's disease

Huntingtons disease (HD) is a fatal neurodegenerative disorder that is caused by the expansion of CAG repeats in the HTT gene, which results in a long polyglutamine (polyQ) tract in the huntingtin protein (HTT). In this study, we searched for networks of deregulated RNAs that contribute to initial transcriptional changes in HD neuronal cells and HTT-deficient cells. We used RNA-seq (including small RNA sequencing) to analyze a set of isogenic, human induced pluripotent stem cell (iPSC)-derived neural stem cells (NSCs); and we observed numerous changes in gene expression and substantial dysregulation of miRNA expression in HD and HTT-knockout (HTT-KO) cell lines. The gene set that was upregulated in both HD and HTT-KO cells was enriched in genes that are associated with DNA binding and regulation of transcription. For both of these models, we confirmed the substantial upregulation of the transcription factors (TFs) TWIST1, SIX1, TBX1, TBX15, MSX2, MEOX2 and FOXD1 in NSCs and medium spiny neuron (MSN)-like cells. Moreover, we identified miRNAs that were consistently deregulated in HD and HTT-KO NSCs and MSN-like cells, including miR-214, miR-199, and miR-9. We suggest that these miRNAs function in the network that regulates TWIST1 and HTT expression via regulatory feed-forward loop (FFL) in HD. Additionally, we reported that the expression of selected TFs and miRNAs tended to progressively change during the neural differentiation of HD cells, what was not observed in HTT-KO model. Based on comparing the HD and HTT-KO cell lines, we propose that early transcriptional deregulation in HD is largely caused by loss of HTT function.

neuroscience↗

bioRxiv2023

SARS-CoV-2 and its ORF3a, E and M viroporins activate inflammasome in human macrophages and induce of IL-1α in pulmonary epithelial and endothelial cells

Inflammasome assembly is a potent mechanism responsible for the host protection against pathogens, including viruses. When compromised, it can allow viral replication, while when disrupted, it can perpetuate pathological responses by IL-1 signaling and pyroptotic cell death. SARS-CoV-2 infection was shown to activate inflammasome in the lungs of COVID-19 patients, however, potential mechanisms responsible for this response are not fully elucidated. In this study, we investigated the effects of ORF3a, E and M SARS-CoV-2 viroporins in the inflammasome activation in major populations of alveolar sentinel cells: macrophages, epithelial and endothelial cells. We demonstrated that each viroporin is capable of activation of the inflammasome in macrophages to trigger cell death and IL-1 release from epithelial and endothelial cells. Small molecule NLRP3 inflammasome inhibitors reduced IL-1 release but weakly affected the pyroptosis. Importantly, we discovered that while SARS-CoV-2 could not infect the pulmonary microvascular endothelial cells it induced IL-1 and IL-33 release. Together, these findings highlight the essential role of macrophages as the major inflammasome-activating cell population in the lungs and point to endothelial cell expressed IL-1 as a potential novel component driving the pulmonary immunothromobosis in COVID-19.

immunology↗