Predicting disease-related MRI patterns of multiple sclerosis through GAN-based image editing.

INTRODUCTION: Multiple sclerosis (MS) is a complex neurodegenerative disorder that affects the brain and spinal cord. In this study, we applied a deep learning-based approach using the StyleGAN model to explore patterns related to MS and predict disease progression in magnetic resonance images (MRI). METHODS: We trained the StyleGAN model unsupervised using T1-weighted GRE MR images and diffusion-based ADC maps of MS patients and healthy controls. We then used the trained model to resample MR images from real input data and modified them by manipulations in the latent space to simulate MS progression. We analyzed the resulting simulation-related patterns mimicking disease progression by comparing the intensity profiles of the original and manipulated images and determined the brain parenchymal fraction (BPF). RESULTS: Our results show that MS progression can be simulated by manipulating MR images in the latent space, as evidenced by brain volume loss on both T1-weighted and ADC maps and increasing lesion extent on ADC maps. CONCLUSION: Overall, this study demonstrates the potential of the StyleGAN model in medical imaging to study image markers and to shed more light on the relationship between brain atrophy and MS progression through corresponding manipulations in the latent space.

TREM-2 mediates dendritic cell-induced NO to suppress Th17 activation and ameliorate chronic kidney diseases.

Chronic kidney disease (CKD) is a global public health issue. CKD is caused by the infiltration of various myeloid cell types into renal tissue, resulting in renal fibrosis and tubular atrophy. Unilateral ureteral obstruction (UUO) surgery in mice is a model of CKD and characterized by high expression of the anti-inflammatory receptor, Triggering receptor expressed on myeloid cells 2 (TREM-2), on myeloid cells in affected kidneys. Here, we show that iNOS expression and nitric oxide (NO) induction were decreased in Trem-2-/- bone marrow-derived DCs (BMDCs) and in Trem-2 knockdown DC2.4 cells stimulated in vitro with LPS. The nitration of RORγt was decreased in T cells co-cultured with LPS-stimulated Trem-2-/- BMDCs, enhancing IL-17 production. UUO-treated Trem-2-/- mice displayed aggravated renal pathogenesis accompanied by greater neutrophil infiltration and enhanced Th17 cells differentiation, phenotypes that could be rescued by the administration of L-arginine (a biological precursor of NO). Our data identify a key mechanism underlying TREM-2-mediated NO to modulate the cellular crosstalk between dendritic cells, Th17, and neutrophils. Furthermore, we also reveal TREM-2 as a potential novel target for the development of anti-inflammatory drugs in CKD treatment. KEY MESSAGES: The expression of TREM-2 is increased in nephritis TREM-2+ DCs maintain NO production to negatively regulate Th17 differentiation The severe pathologies of nephritis can be rescued by L-arginine supplementation.

PP4 deficiency leads to DNA replication stress that impairs immunoglobulin class switch efficiency.

The serine/threonine phosphatase PP4 has been implicated in DNA damage repair and cell cycle regulation through its dephosphorylation of specific substrates. We previously showed that PP4 is required for mouse B cell development, germinal center (GC) formation and immunoglobulin (Ig) class switch recombination (CSR). Here, we investigate the mechanisms underlying this requirement and demonstrate that murine PP4-deficient B lymphocytes have a defect in cell proliferation. Strikingly, the DNA damage response pathway that involves ATM/p53 and is linked to cell cycle arrest and impaired cell survival is strongly induced in these mutant B cells. In response to LPS + IL-4, stimuli that trigger IgG1 production, these PP4-deficient B cells show inefficient phosphorylation of ATR, leading to reduced retention of γH2AX-NBS1 complexes at sites of DNA damage, and compromised switching to IgG1. However, beyond the cell proliferation phase, conditional deletion of PP4 under the control of AID/cre completely restores normal IgG1 production in mutant B cell cultures. In vivo, co-deletion of PP4 and p53 by AID/cre partially rescues switching to IgG1 in B cells of mice immunized with TNP-KLH. Our findings establish that PP4 is indispensable for preventing DNA replication stress that could interfere with CSR, thereby promoting antibody switching during the humoral immune response.

DUSP6 mediates T cell receptor-engaged glycolysis and restrains TFH cell differentiation.

Activated T cells undergo metabolic reprogramming and effector-cell differentiation but the factors involved are unclear. Utilizing mice lacking DUSP6 (DUSP6-/-), we show that this phosphatase regulates T cell receptor (TCR) signaling to influence follicular helper T (TFH) cell differentiation and T cell metabolism. In vitro, DUSP6-/- CD4+ TFH cells produced elevated IL-21. In vivo, TFH cells were increased in DUSP6-/- mice and in transgenic OTII-DUSP6-/- mice at steady state. After immunization, DUSP6-/- and OTII-DUSP6-/- mice generated more TFH cells and produced more antigen-specific IgG2 than controls. Activated DUSP6-/- T cells showed enhanced JNK and p38 phosphorylation but impaired glycolysis. JNK or p38 inhibitors significantly reduced IL-21 production but did not restore glycolysis. TCR-stimulated DUSP6-/- T cells could not induce phosphofructokinase activity and relied on glucose-independent fueling of mitochondrial respiration. Upon CD28 costimulation, activated DUSP6-/- T cells did not undergo the metabolic commitment to glycolysis pathway to maintain viability. Unexpectedly, inhibition of fatty acid oxidation drastically lowered IL-21 production in DUSP6-/- TFH cells. Our findings suggest that DUSP6 connects TCR signaling to activation-induced metabolic commitment toward glycolysis and restrains TFH cell differentiation via inhibiting IL-21 production.

C5L2 is required for C5a-triggered receptor internalization and ERK signaling.

C5L2 is a receptor that binds to C5a and belongs to the family of G protein-coupled receptors, but its role in physiological C5a-mediated responses remains under debate. Here we show that, like the canonical C5a receptor C5aR, C5L2 plays a pro-inflammatory role in a murine model of acute experimental colitis. We demonstrate that C5L2 physically interacts with C5aR and is required for optimal C5a-mediated C5aR internalization and associated ERK activation. Abrogation of C5a-induced receptor internalization by treatment with the dynamin inhibitor dynasore(TM) impaired C5a-induced MEK and ERK signaling. Although the presence of C5aR alone was sufficient to recruit the scaffold protein ß-arrestin1 to the cell membrane in response to C5a stimulation, it was inadequate to mediate AP2 recruitment and subsequent C5aR internalization. Expression of C5L2 allowed normal internalization of C5aR in response to C5a stimulation, followed by normal ERK signaling. Thus, our work reveals an essential role for C5L2 in C5a-triggered, AP2-dependent C5aR internalization and downstream ERK signaling.