Biology subjects

Marquardt, K.

Publications and source records attributed to Marquardt, K..

3 recordsLinked to original sources

bioRxiv2024

Enhanced Fear Extinction Through Infralimbic Perineuronal Net Digestion: The Modulatory Role of Adolescent Alcohol Exposure

Perineuronal nets (PNNs) are specialized components of the extracellular matrix that play a critical role in learning and memory. In a Pavlovian fear conditioning paradigm, degradation of PNNs affects the formation and storage of fear memories. This study examined the impact of adolescent intermittent ethanol (AIE) exposure by vapor inhalation on the expression of PNNs in the adult rat prelimbic (PrL) and infralimbic (IfL) subregions of the medial prefrontal cortex. Results indicated that following AIE, the total number of PNN positive cells in the PrL cortex increased in layer II/III but did not change in layer V. Conversely, in the IfL cortex, the number of PNN positive cells decreased in layer V, with no change in layer II/III. In addition, the intensity of PNN staining was significantly altered by AIE exposure, which narrowed the distribution of signal intensity, reducing the number of high and low intensity PNNs. Given these changes in PNNs, the next experiment assessed the effects of AIE and PNN digestion on extinction of a conditioned fear memory. In Air control rats, digestion of PNNs by bilateral infusion of Chondroitinase ABC (ChABC) into the IfL cortex enhanced fear extinction and reduced contextual fear renewal. In contrast, both fear extinction learning and contextual fear renewal remained unchanged following PNN digestion in AIE exposed rats. These results highlight the sensitivity of prefrontal PNNs to adolescent alcohol exposure and suggest that ChABC-induced plasticity is reduced in the IfL cortex following AIE exposure.

neuroscience↗

bioRxiv2023

Autoimmunity associated allele of tyrosine phosphatase gene PTPN22 enhances anti-viral immunity

AbstractThe 1858C>T allele of the tyrosine phosphatase PTPN22 is present in 5-10% of the North American population and is strongly associated with numerous autoimmune diseases. Although research has been done to define how this allele potentiates autoimmunity, the influence PTPN22 and its pro-autoimmune allele has in anti-viral immunity remains poorly defined. Here, we use single cell RNA- sequencing and functional studies to interrogate the impact of this pro- autoimmune allele on anti-viral immunity during Lymphocytic Choriomeningitis Virus clone 13 (LCMV-cl13) infection. Mice homozygous for this allele (PEP- 619WW) clear the LCMV-cl13 virus whereas wildtype (PEP-WT) mice cannot. This is associated with enhanced anti-viral CD4 T cell responses and a more immunostimulatory CD8- cDC phenotype. Adoptive transfer studies demonstrated that PEP-619WW enhanced anti-viral CD4 T cell function through virus-specific CD4 T cell intrinsic and extrinsic mechanisms. Taken together, our data show that the pro-autoimmune allele of Ptpn22 drives a beneficial anti-viral immune response thereby preventing what is normally a chronic virus infection. Author SummaryPTPN22 and its alternative allele, 1858C>T, has largely been studied in the context of autoimmunity. Through these studies, researchers defined roles for PTPN22 in regulating T lymphocyte activation, myeloid cell cytokine production, and macrophage polarization. Despite these immune pathways being critical for anti-viral immunity, little work has studied how this allele impacts virus infection. In this study, we examine gene expression and function of immune cell subsets to demonstrate how a common allelic variant of PTPN22, which strongly increases the risk of autoimmune disease, promotes successful clearance of an otherwise chronic viral infection.

immunology↗

bioRxiv2021

Pro-autoimmune allele of tyrosine phosphatase, PTPN22, enhances tumor immunity

The 1858C>T allele of the tyrosine phosphatase PTPN22 (causing amino acid substitution R620W in encoded protein Lyp) is present in 5-10% of the North American population and is strongly associated with numerous autoimmune diseases. Although much research has been done to define how this allele potentiates autoimmunity, the influence PTPN22 and its pro-autoimmune allele has in tumor immunity is poorly defined. To interrogate the role this allele may have in the anti-tumor immune response, we used CRISPR/Cas9 to generate mice in which the ortholog of Lyp, PEP, is mutated at position 619 to produce the relevant pro-autoimmune mutation (R619W). Results of this study show that mice homozygous for this alteration (PEP-619WW) resist tumor growth as compared with wildtype mice. Consistent with these results, tumors from PEP-619WW mice have more CD45 infiltrates containing more activated CD8 T cell and CD4 T cells. Additionally, there are more cDC1 cells and less MDSCs in tumors from PEP-619WW mice. Interestingly, the tumor infiltrating PEP-619WW cDC1s have decreased PD-L1 expression compared to cDC1s from PEP-WT mice. Taken together, our data show that the pro-autoimmune allele of Ptpn22 drives a strong anti-tumor response in innate and adaptive immune cells resulting in superior control of tumors.

immunology↗