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Transcriptomic analysis of loss of Gli1 in neural stem cells responding to demyelination in the mouse brain

Samanta, Jayshree; Silva, Hernandez Moura; Lafaille, Juan J; Salzer, James L
In the adult mammalian brain, Gli1 expressing neural stem cells reside in the subventricular zone and their progeny are recruited to sites of demyelination in the white matter where they generate new oligodendrocytes, the myelin forming cells. Remarkably, genetic loss or pharmacologic inhibition of Gli1 enhances the efficacy of remyelination by these neural stem cells. To understand the molecular mechanisms involved, we performed a transcriptomic analysis of this Gli1-pool of neural stem cells. We compared murine NSCs with either intact or deficient Gli1 expression from adult mice on a control diet or on a cuprizone diet which induces widespread demyelination. These data will be a valuable resource for identifying therapeutic targets for enhancing remyelination in demyelinating diseases like multiple sclerosis.
PMID: 34711861
ISSN: 2052-4463
CID: 5042772

c-MAF-dependent perivascular macrophages regulate diet-induced metabolic syndrome

Moura Silva, Hernandez; Kitoko, Jamil Zola; Queiroz, Camila Pereira; Kroehling, Lina; Matheis, Fanny; Yang, Katharine Lu; Reis, Bernardo S; Ren-Fielding, Christine; Littman, Dan R; Bozza, Marcelo Torres; Mucida, Daniel; Lafaille, Juan J
[Figure: see text].
PMID: 34597123
ISSN: 2470-9468
CID: 5061682

Food colorants metabolized by commensal bacteria promote colitis in mice with dysregulated expression of interleukin-23

He, Zhengxiang; Chen, Lili; Catalan-Dibene, Jovani; Bongers, Gerold; Faith, Jeremiah J; Suebsuwong, Chalada; DeVita, Robert J; Shen, Zeli; Fox, James G; Lafaille, Juan J; Furtado, Glaucia C; Lira, Sergio A
Both genetic predisposition and environmental factors appear to play a role in inflammatory bowel disease (IBD) development. Genetic studies in humans have linked the interleukin (IL)-23 signaling pathway with IBD, but the environmental factors contributing to disease have remained elusive. Here, we show that the azo dyes Red 40 and Yellow 6, the most abundant food colorants in the world, can trigger an IBD-like colitis in mice conditionally expressing IL-23, or in two additional animal models in which IL-23 expression was augmented. Increased IL-23 expression led to generation of activated CD4+ T cells that expressed interferon-γ and transferred disease to mice exposed to Red 40. Colitis induction was dependent on the commensal microbiota promoting the azo reduction of Red 40 and generation of a metabolite, 1-amino-2-naphthol-6-sulfonate sodium salt. Together these findings suggest that specific food colorants represent novel risk factors for development of colitis in mice with increased IL-23 signaling.
PMID: 33989521
ISSN: 1932-7420
CID: 4867852

Learning-Dependent Dendritic Spine Plasticity Is Impaired in Spontaneous Autoimmune Encephalomyelitis

Huang, Lianyan; Lafaille, Juan J; Yang, Guang
Cognitive impairment is often observed in multiple sclerosis and its animal models, experimental autoimmune encephalomyelitis (EAE). Using mice with immunization-induced EAE, we have previously shown that the stability of cortical synapses is markedly decreased before the clinical onset of EAE. In this study, we examined learning-dependent structural synaptic plasticity in a spontaneous EAE model. Transgenic mice expressing myelin basic protein-specific T cell receptor genes develop EAE spontaneously at around 8 weeks of age. Using in vivo two-photon microscopy, we found that the elimination and formation rates of postsynaptic dendritic spines in somatosensory and motor cortices increased weeks before detectable signs of EAE and remained to be high during the disease onset. Despite the elevated basal spine turnover, motor learning-induced spine formation was reduced in presymptomatic EAE mice, in line with their impaired ability to retain learned motor skills. Additionally, we found a substantial elevation of IFN-γ mRNA in the brain of 4-week-old presymptomatic mice, and treatment of anti-IFN-γ antibody reduced dendritic spine elimination in the cortex. Together, these findings reveal synaptic instability and failure to form new synapses after learning as early brain pathology of EAE, which may contribute to cognitive and behavioral deficits seen in autoimmune diseases.
PMID: 33949123
ISSN: 1932-846x
CID: 4858952

CSF1R inhibition depletes tumor-associated macrophages and attenuates tumor progression in a mouse sonic Hedgehog-Medulloblastoma model

Tan, I-Li; Arifa, Raquel Duque Nascimento; Rallapalli, Harikrishna; Kana, Veronika; Lao, Zhimin; Sanghrajka, Reeti Mayur; Sumru Bayin, N; Tanne, Antoine; Wojcinski, Alexandre; Korshunov, Andrey; Bhardwaj, Nina; Merad, Miriam; Turnbull, Daniel H; Lafaille, Juan J; Joyner, Alexandra L
The immune microenvironment of tumors can play a critical role in promoting or inhibiting tumor progression depending on the context. We present evidence that tumor-associated macrophages/microglia (TAMs) can promote tumor progression in the sonic hedgehog subgroup of medulloblastoma (SHH-MB). By combining longitudinal manganese-enhanced magnetic resonance imaging (MEMRI) and immune profiling of a sporadic mouse model of SHH-MB, we found the density of TAMs is higher in the ~50% of tumors that progress to lethal disease. Furthermore, reducing regulatory T cells or eliminating B and T cells in Rag1 mutants does not alter SHH-MB tumor progression. As TAMs are a dominant immune component in tumors and are normally dependent on colony-stimulating factor 1 receptor (CSF1R), we treated mice with a CSF1R inhibitor, PLX5622. Significantly, PLX5622 reduces a subset of TAMs, prolongs mouse survival, and reduces the volume of most tumors within 4 weeks of treatment. Moreover, concomitant with a reduction in TAMs the percentage of infiltrating cytotoxic T cells is increased, indicating a change in the tumor environment. Our studies in an immunocompetent preclinical mouse model demonstrate TAMs can have a functional role in promoting SHH-MB progression. Thus, CSF1R inhibition could have therapeutic potential for a subset of SHH-MB patients.
PMID: 33159168
ISSN: 1476-5594
CID: 4664582

Spleen plays a major role in DLL4-driven acute T-cell lymphoblastic leukemia

Xiong, Huizhong; Mancini, Maicol; Gobert, Michael; Shen, Shiqian; Furtado, Glaucia C; Lira, Sergio A; Parkhurst, Christopher N; Garambois, Veronique; Brengues, Muriel; Tadokoro, Carlos E; Trimarchi, Thomas; Gómez-López, Gonzalo; Singh, Amartya; Khiabanian, Hossein; Minuzzo, Sonia; Indraccolo, Stefano; Lobry, Camille; Aifantis, Iannis; Herranz, Daniel; Lafaille, Juan J; Maraver, Antonio
The Notch pathway is highly active in almost all patients with T-cell acute lymphoblastic leukemia (T-ALL), but the implication of Notch ligands in T-ALL remains underexplored. Methods: We used a genetic mouse model of Notch ligand delta like 4 (DLL4)-driven T-ALL and performed thymectomies and splenectomies in those animals. We also used several patient-derived T-ALL (PDTALL) models, including one with DLL4 expression on the membrane and we treated PDTALL cells in vitro and in vivo with demcizumab, a blocking antibody against human DLL4 currently being tested in clinical trials in patients with solid cancer. Results: We show that surgical removal of the spleen abrogated T-ALL development in our preclinical DLL4-driven T-ALL mouse model. Mechanistically, we found that the spleen, and not the thymus, promoted the accumulation of circulating CD4+CD8+ T cells before T-ALL onset, suggesting that DLL4-driven T-ALL derives from these cells. Then, we identified a small subset of T-ALL patients showing higher levels of DLL4 expression. Moreover, in mice xenografted with a DLL4-positive PDTALL model, treatment with demcizumab had the same therapeutic effect as global Notch pathway inhibition using the potent γ-secretase inhibitor dibenzazepine. This result demonstrates that, in this PDTALL model, Notch pathway activity depends on DLL4 signaling, thus validating our preclinical mouse model. Conclusion: DLL4 expression in human leukemic cells can be a source of Notch activity in T-ALL, and the spleen plays a major role in a genetic mouse model of DLL4-driven T-ALL.
PMID: 33408769
ISSN: 1838-7640
CID: 4739112

Niche-Selective Inhibition of Pathogenic Th17 Cells by Targeting Metabolic Redundancy

Wu, Lin; Hollinshead, Kate E R; Hao, Yuhan; Au, Christy; Kroehling, Lina; Ng, Charles; Lin, Woan-Yu; Li, Dayi; Silva, Hernandez Moura; Shin, Jong; Lafaille, Juan J; Possemato, Richard; Pacold, Michael E; Papagiannakopoulos, Thales; Kimmelman, Alec C; Satija, Rahul; Littman, Dan R
Targeting glycolysis has been considered therapeutically intractable owing to its essential housekeeping role. However, the context-dependent requirement for individual glycolytic steps has not been fully explored. We show that CRISPR-mediated targeting of glycolysis in T cells in mice results in global loss of Th17 cells, whereas deficiency of the glycolytic enzyme glucose phosphate isomerase (Gpi1) selectively eliminates inflammatory encephalitogenic and colitogenic Th17 cells, without substantially affecting homeostatic microbiota-specific Th17 cells. In homeostatic Th17 cells, partial blockade of glycolysis upon Gpi1 inactivation was compensated by pentose phosphate pathway flux and increased mitochondrial respiration. In contrast, inflammatory Th17 cells experience a hypoxic microenvironment known to limit mitochondrial respiration, which is incompatible with loss of Gpi1. Our study suggests that inhibiting glycolysis by targeting Gpi1 could be an effective therapeutic strategy with minimum toxicity for Th17-mediated autoimmune diseases, and, more generally, that metabolic redundancies can be exploited for selective targeting of disease processes.
PMID: 32615085
ISSN: 1097-4172
CID: 4504552

Regulatory T Cells License Macrophage Pro-Resolving Functions During Atherosclerosis Regression

Sharma, Monika; Schlegel, Martin Paul; Afonso, Milessa Silva; Brown, Emily J; Rahman, Karishma; Weinstock, Ada; Sansbury, Brian; Corr, Emma M; van Solingen, Coen; Koelwyn, Graeme; Shanley, Lianne C; Beckett, Lauren; Peled, Daniel; Lafaille, Juan J; Spite, Matthew; Loke, P'ng; Fisher, Edward A; Moore, Kathryn J
Rationale: Regression of atherosclerosis is an important clinical goal, however the pathways that mediate the resolution of atherosclerotic inflammation and reversal of plaques are poorly understood. Regulatory T cells (Tregs) have been shown to be atheroprotective, yet the numbers of these immunosuppressive cells decrease with disease progression, and whether they contribute to atherosclerosis regression is not known. Objective: We investigated the roles of Tregs in the resolution of atherosclerotic inflammation, tissue remodeling and plaque contraction during atherosclerosis regression. Methods and Results: Using multiple independent mouse models of atherosclerosis regression, we demonstrate that an increase in plaque Tregs is a common signature of regressing plaques. Single cell RNA-sequencing of plaque immune cells from revealed that Tregs from regressing plaques shared some similarity with splenic Tregs, but were distinct from skin and colon Tregs supporting recent findings of tissue-dependent Treg heterogeneity. Unlike Tregs from progressing plaques that expressed markers of natural Tregs derived from the thymus, Tregs in regressing plaques lacked Nrp1 and Helios expression, suggesting that they are induced in the periphery during lipid lowering therapy. To test whether Tregs are required for resolution of atherosclerotic inflammation and plaque regression, Tregs were depleted using CD25 monoclonal antibody in atherosclerotic mice during apolipoprotein B anti-sense oligonucleotide-mediated lipid lowering. Morphometric analyses revealed that Treg depletion blocked plaque remodeling and contraction, and impaired hallmarks of inflammation resolution including dampening of the Th1 response, alternative activation of macrophages, efferocytosis, and upregulation of specialized pro-resolving lipid mediators. Conclusions: Our data establish essential roles for Tregs in resolving atherosclerotic cardiovascular disease and provide mechanistic insight into the pathways governing plaque remodeling and regression of disease.
PMID: 32336197
ISSN: 1524-4571
CID: 4411712

P2X7 receptor inhibition ameliorates dendritic spine pathology and social behavioral deficits in Rett syndrome mice

Garré, Juan Mauricio; Silva, Hernandez Moura; Lafaille, Juan J; Yang, Guang
Dysregulated immunity has been implicated in the pathogenesis of neurodevelopmental disorders but its contribution to synaptic and behavioral deficits in Rett syndrome (RTT) remains unknown. P2X7 receptors (P2X7Rs) are unique purinergic receptors with pro-inflammatory functions. Here, we report in a MECP2-deficient mouse model of RTT that the border of the cerebral cortex exhibits increased number of inflammatory myeloid cells expressing cell-surface P2X7Rs. Total knockout of P2X7Rs in MECP2 deficient mice decreases the number of inflammatory myeloid cells, restores cortical dendritic spine dynamics, and improves the animals' neurological function and social behavior. Furthermore, either genetic depletion of P2X7Rs in bone-marrow derived leukocytes or pharmacological block of P2X7Rs primarily outside of the central nervous system parenchyma, recapitulates the beneficial effects of total P2X7R depletion on the social behavior. Together, our results highlight the pathophysiological roles of P2X7Rs in a mouse model of RTT.
PMID: 32286307
ISSN: 2041-1723
CID: 4401292

Vasculature-associated fat macrophages readily adapt to inflammatory and metabolic challenges

Silva, Hernandez Moura; Báfica, André; Rodrigues-Luiz, Gabriela Flavia; Chi, Jingyi; Santos, Patricia d'Emery Alves; Reis, Bernardo S; Hoytema van Konijnenburg, David P; Crane, Audrey; Arifa, Raquel Duque Nascimento; Martin, Patricia; Mendes, Daniel Augusto G B; Mansur, Daniel Santos; Torres, Victor J; Cadwell, Ken; Cohen, Paul; Mucida, Daniel; Lafaille, Juan J
Tissue-resident macrophages are the most abundant immune cell population in healthy adipose tissue. Adipose tissue macrophages (ATMs) change during metabolic stress and are thought to contribute to metabolic syndrome. Here, we studied ATM subpopulations in steady state and in response to nutritional and infectious challenges. We found that tissue-resident macrophages from healthy epididymal white adipose tissue (eWAT) tightly associate with blood vessels, displaying very high endocytic capacity. We refer to these cells as vasculature-associated ATMs (VAMs). Chronic high-fat diet (HFD) results in the accumulation of a monocyte-derived CD11c+CD64+ double-positive (DP) macrophage eWAT population with a predominant anti-inflammatory/detoxifying gene profile, but reduced endocytic function. In contrast, fasting rapidly and reversibly leads to VAM depletion, while acute inflammatory stress induced by pathogens transiently depletes VAMs and simultaneously boosts DP macrophage accumulation. Our results indicate that ATM populations dynamically adapt to metabolic stress and inflammation, suggesting an important role for these cells in maintaining tissue homeostasis.
PMID: 30862706
ISSN: 1540-9538
CID: 3733132