Mireia Guerau

• PharmD, PhD
• Professor (Assistant) at The Ohio State University

We have previously shown that short-term (3-day) high fat diet (HFD) consumption induces a neuroinflammatory response and subsequent impairment of long-term memory in aged, but not young adult, male rats. However, the immune cell phenotypes driving this proinflammatory response are not well understood. Previously, we showed that microglia isolated...

The field of sterol and oxysterol biology in lung disease has recently gained attention, revealing a unique need for sterol uptake and metabolism in the lung. The presence of cholesterol transport, biosynthesis, and sterol/oxysterol-mediated signaling in immune cells suggests a role in immune regulation. In support of this idea, statin drugs that i...

Akt is a PI3K-activated serine-threonine kinase that exists in three distinct isoforms. Akt’s expression in most immune cells, either at baseline or upon activation, reflects its importance in the immune system. While Akt is most highly expressed in innate immune cells, it plays crucial roles in both innate and adaptive immune cell development and/...

Severe asthma is characterized by steroid insensitivity and poor symptom control and is responsible for most asthma-related hospital costs. Therapeutic options remain limited, in part due to limited understanding of mechanisms driving severe asthma. Increased arginine methylation, catalyzed by protein arginine methyltransferases (PRMTs), is increas...

Minority groups face barriers in accessing quality health care, professional advancement, and representation in immunology research efforts as a result of institutional racism that if unaddressed can perpetuate a lack of diversity. In 2021, the AAI Minority Affairs Committee convened a cross section of academic and industry scientists from underrep...

Protein arginine methyltransferase (PRMT) 5 is the type 2 methyltransferase catalyzing symmetric dimethylation of arginine. PRMT5 inhibition or deletion in CD4 Th cells reduces TCR engagement-induced IL-2 production and Th cell expansion and confers protection against experimental autoimmune encephalomyelitis, the animal model of multiple sclerosis...

Severe asthma is characterized by steroid insensitivity and poor symptom control, and is responsible for the majority of asthma-related hospital costs. Therapeutic options remain limited, in part due to a lack of mechanisms driving severe asthma phenotypes. Increased arginine methylation, catalyzed by protein arginine methyltransferases (PRMTs), is...

Protein Arginine Methyltransferase (PRMT) 5 is the major type 2 methyltransferase catalyzing symmetric dimethylation (SDM) of arginine. PRMT5 inhibition or deletion in CD4 Th cells reduces TcR engagement-induced IL-2 production and Th cell expansion and confers protection against experimental autoimmune encephalomyelitis (EAE), the animal model of...

Multiple Sclerosis (MS) is a debilitating central nervous system disorder associated with inflammatory T cells. Activation and expansion of inflammatory T cells is thought to be behind MS relapses and influence disease severity. Protein arginine N-methyltransferase 5 (PRMT5) is a T cell activation-induced enzyme that symmetrically dimethylates prot...

Protein Arginine Methyltransferase (PRMT) 5 catalyzes symmetric dimethylation of arginine, a post-translational modification involved in cancer and embryonic development. The mechanisms by which PRMT5 modulates T helper (Th) cell activity are still not completely understood. Here we find that PRMT5 in T cells promotes spliceosome component methylat...

Background Inflammation in chronic active lesions occurs behind a closed blood–brain barrier and cannot be detected with MRI. Activated microglia are highly enriched for iron and can be visualized with quantitative susceptibility mapping (QSM), an MRI technique used to delineate iron. Objective To characterize the histopathological correlates of d...

CD38 is a molecule that can act as an enzyme, with NAD-depleting and intracellular signaling activity, or as a receptor with adhesive functions. CD38 can be found expressed either on the cell surface, where it may face the extracellular milieu or the cytosol, or in intracellular compartments, such as endoplasmic reticulum, nuclear membrane, and mit...

Protein arginine methyltransferase 5 (PRMT5) is the major methyltransferase (MT) catalyzing symmetric dimethylation (SDM). PRMT5 regulates developmental, homeostatic and disease processes in vertebrates and invertebrates, and a carcinogenic role has been observed in mammals. Recently, tools generated for PRMT5 loss of function have allowed research...

T cells undergo metabolic rewiring to meet their bioenergetic, biosynthetic and redox demands following antigen stimulation. To fulfil these needs, effector T cells must adapt to fluctuations in environmental nutrient levels at sites of infection and inflammation. Here, we show that effector T cells can utilize inosine, as an alternative substrate,...

Protein Arginine Methyltransferase (PRMT) 5 is a type-II methyltransferase involved in oncogenesis, embryonic and hematopoietic development. However, the role of PRMT5 T-cell biology is only now coming into focus. To evaluate PRMT5’s functions in T-cells, we have developed a conditional knock-out (KO) model that allow for a deletion of PRMT5 during...

Protein Arginine Methyltransferase (PRMT) 5 is an enzyme catalyzing symmetric dimethylation (SDM) of arginine. This post-translational modification is known to be involved in oncogenesis and embryonic development. Our previous work has shown that PRMT5 is induced during T cell activation. However, the role and mechanisms by which PRMT5 modulates T...

PRMT5 catalyzes symmetric dimethylation (SDM) on arginine residues. PRMT5 methylates histone H3 and H4 producing remodeling of chromatin and regulation of gene transcription. PRMT5 is induced after T cell activation. Furthermore, both PRMT5 inhibitors and PRMT5 knockdown impair T cell proliferation and activation. However, the role of PRMT5 in T ce...

Protein arginine methyltransferase 5 (PRMT5) catalyzes symmetric dimethylation (SDM) of arginine, a posttranslational modification involved in oncogenesis and embryonic development. However, the role and mechanisms by which PRMT5 modulates Th cell polarization and autoimmune disease have not yet been elucidated. Here, we found that PRMT5 promoted S...

Protein Arginine Methyltransferase (PRMT) 5 catalyzes symmetric dimethylation of arginine, a post-translational modification involved in cancer and embryonic development. However, the role of PRMT5 in T helper (Th) cell polarization and Th cell-mediated disease has not yet been elucidated. Here we report that PRMT5 is necessary for Th17 differentia...

Abdominal aortic aneurysm (AAA) is characterized by transmural infiltration of myeloid cells at the vascular injury site. Previously, we reported preventive effects of Notch deficiency on the development of AAA by reduction of infiltrating myeloid cells. In this study, we examined if Notch inhibition attenuates the progression of pre-established AA...

CD4+ T helper 1 (Th1) cells producing interferon-γ (IFN-γ) are critical for the resolution of visceral leishmaniasis (VL). Micro RNA 155 (miR155) promotes CD4+ Th1 response and IFN-γ production by targeting Suppressor of cytokine signaling-1 (SOCS1) and inositol polyphosphate-5-phosphatase (SHIP-1) and therefore could play a role in the resolution...

Multiple sclerosis (MS) is a debilitating autoimmune disease of the central nervous system (CNS) mediated by CD4+ T cells. Clinical data has provided evidence that MS patient T cells display an activated or memory phenotype and genome-wide association studies (GWAS) have identified single nucleotide polymorphisms linked to NF-kB complex and MYC gen...

Severe asthma affects 2.4 million Americans and 23.8 million people worldwide and accounts for the majority of total asthma hospital costs. Most severe asthma is mediated by Th17/neutrophilic responses, alone or combined with Th2 and/or Th1 responses. In contrast, Treg responses are deficient. Protein Arginine Methyl Transferase (PRMT) 5 catalyzes...

Multiple sclerosis is an autoimmune disease of the central nervous system (CNS) mediated by CD4⁺ T cells and modeled via experimental autoimmune encephalomyelitis (EAE). Inhibition of PRMT5, the major Type II arginine methyltransferase, suppresses pathogenic T cell responses and EAE. PRMT5 is transiently induced in proliferating memory inflammatory...

miRNA expression in naive Th cells. (A) Cos-7 cells were transfected with empty luciferase plasmid (without Prmt5 3′UTR) and indicated miRNAs. Data are expressed as a relative ratio of firefly luciferase to renilla luciferase activity. Data are pooled from 3 independent experiments. (B–G) Naive Th cells were activated with anti-CD3/CD28 and miR-15a...

NF-κB/MYC/mTOR axis does not regulate Prmt5 transcript or Prmt5-targeting miRNA expression in murine memory Th cells. (A–F) Memory murine MBP TcR Tg Th1 were activated anti-CD3/CD28 for 8 h in the presence of NF-κB inhibitor Bay11 (NF-κBi) (A,B), MYC inhibitor 10058-F4 (MYCi) (C,D), or mTOR inhibitor rapamycin (mTORi) (E,F), and Prmt5 (A,C,E) and M...

miRNA expression human memory Th1 and Th2 cells. Human memory Th1 (A–F) and Th2 (G–L) were activated with anti-CD3/CD28 and miR-96 (A,G), miR-15a, (B,H), miR-15b (C,I), miR-195 (D,J), miR-16 (E,K), and miR-322/424 (F,L) expression was measured by real time PCR. Data are representative of three independent experiments. Error bars indicate SEM. *p <...

This study was conducted to characterize the effect of miR-155 overexpression on white matter sparing and lesion size following contusion injury of spinal cord in mice. 60 C57BL/6J wild-type and 60 B6.Cg miR-155 knockout mice were used to induce moderate to severe contusive spinal cord injury at T9 segment. All used mice were female, 8–20 weeks old...

There are no significant associations between CD38 expression and age, gender, or race. CD38 mean fluorescence intensity (MFI) (A–C) and % CD38hi cells (D–F) from healthy donors (HD) were analyzed to determine if age, gender or race affected CD38 protein load or surface expression. (A,D) Correlation analyses of SLE Disease Activity Index score with...

Representative graphs with absolute values from individual experiments for Figure 3. Human monocyte-derived macrophages (MDMs) were treated with 15 µM rhein or DMSO control (A), 25 µM apigenin or DMSO (B), or transfected with 100 µM CD38 siRNA cocktail or nonsense siRNA control (C) on day 5. On day 6, they were activated with LPS + IFN-γ for an add...

Lactate dehydrogenase (LDH) remains unchanged in treatment groups compared with corresponding experiment vehicle control or nonsense siRNA. (A–C) Quantification of LDH activity from monocyte-derived macrophage supernatants of 15 µM rhein-treated (A), 25 µM apigenin-treated (B), or CD38 siRNA-transfected (C) conditions compared with control conditio...

CD38+ T cell and B cell percentages in patients with SLE. (A) Gating strategy: peripheral blood mononuclear cells isolated from healthy donors or SLE patients (panel 1) were gated for CD45+ cells (panel 2), then CD20+ or CD3+ cells (panel 3), and subsequently CD38+ cells (B,C). (B,C) Quantification of CD45+CD20+CD38+ (B) or CD45+CD3+CD38+ (C) cells...

Macrophages and their monocyte precursors mediate innate immune responses and can promote a spectrum of phenotypes from pro-inflammatory to pro-resolving. Currently, there are few markers that allow for robust dissection of macrophage phenotype. We recently identified CD38 as a marker of inflammatory macrophages in murine in vitro and in vivo model...

Background: Post-transplant lymphoproliferative disease (PTLD) is a significant and often fatal complication of organ transplantation, strongly associated with Epstein-Barr virus (EBV). Severe combined immune-deficient (SCID) mice engrafted with human mononuclear cells (PBMCs) from EBV+ donors spontaneously develop human B cell lymphoproliferative...

Macrophages mediate innate immune responses via a spectrum of phenotypes that range from inflammatory to resolving. We previously identified CD38 as a robust marker of inflammatory macrophages useful in both murine in vitro and in vivo models. We hypothesized that CD38 plays a similar biomarker and/or functional role in human macrophages and autoim...

Multiple sclerosis (MS) is a chronic inflammatory disease of the central nervous system that is the leading cause of disability in 2 million young adults aged 20–40 worldwide. Heightened pro-inflammatory T helper (Th) 1 and Th17 cell responses and deficient Th2 and regulatory T (Treg) cell responses drive myelin sheath damage and disability in MS....

Interleukin 1 is a pleiotropic cytokine that mediates diverse functions through its receptor, type I interleukin 1 receptor (IL-1R1). Most previous studies have focused on the expression and function of IL-1R1 in immune cells. Here we performed a comprehensive mapping of IL-1R1 distribution in multiple peripheral tissues using our IL-1R1 reporter (...

Macrophages and microglia play crucial roles during central nervous system development, homeostasis and acute events such as infection or injury. The diverse functions of tissue macrophages and microglia are mirrored by equally diverse phenotypes. A model of inflammatory/M1 versus a resolution phase/M2 macrophages has been widely used. However, the...

Multiple Sclerosis (MS) is a chronic inflammatory disease of the central nervous system. The inflammatory and neurodegenerative pathways driving MS are modulated by DNA, lysine, and arginine methylation, as evidenced by studies made possible by novel tools for methylation detection or loss of function. We present evidence that MS is associated with...

In the autoimmune disease Multiple Sclerosis (MS), pro-inflammatory, pathogenic T helper (Th) 1 and Th17 responses promote demyelination and disability. MS treatments that preferentially target inflammatory T cell responses may be beneficial to the field. Epigenetic modifications regulate cellular functions and phenotype and inhibition of all methy...

Multiple sclerosis (MS) is an inflammatory disease of the central nervous system. While 2.5 million people are affected by MS worldwide, there is no cure other than ameliorating the symptoms through broad immune suppression, which leads to side effects, including increased risks of infection and cancer development. Therefore, tolerance induction sp...

Helminths cause chronic infections and affect the immune response to unrelated inflammatory diseases. Although helminths have been used therapeutically to ameliorate inflammatory conditions, their anti-inflammatory properties are poorly understood. Alternatively activated macrophages (AAMϕs) have been suggested as the anti-inflammatory effector cel...

In the autoimmune disease multiple sclerosis and its animal model, experimental autoimmune encephalomyelitis (EAE), expansion of pathogenic, myelin-specific Th1 cell populations drives active disease; selectively targeting this process may be the basis for a new therapeutic approach. Previous studies have hinted at a role for protein arginine methy...

Recent studies implicate innate immunity to systemic lupus erythematosus (SLE) pathogenesis. Toll-like receptor (TLR)8 is estrogen-regulated and binds viral ssRNA to stimulate innate immune responses, but recent work indicates that microRNA (miR)-21 within extracellular vesicles (EVs) can also trigger this receptor. Our objective was to examine TLR...

Unlabelled: Axon regeneration after spinal cord injury (SCI) fails due to neuron-intrinsic mechanisms and extracellular barriers including inflammation. microRNA (miR)-155-5p is a small, noncoding RNA that negatively regulates mRNA translation. In macrophages, miR-155-5p is induced by inflammatory stimuli and elicits a response that could be toxic...

Inflammatory M1 spectrum macrophages protect from infection but can cause inflammatory disease and tissue damage, whereas alternatively activated/M2 spectrum macrophages reduce inflammation and promote tissue repair. Modulation of macrophage phenotype may be therapeutically beneficial and requires further understanding of the molecular programs tha...

Genes decreased more than 2-fold in KO M1 vs. KO M0 macrophages. (XLSX)

M1 macrophage markers compared between WT M1vs. WT M0 and KO M1 vs. KO M0 macrophages. (XLSX)

Myeloid cell populations in lymphoid tissues in miR-155 knockout mice. Percentage of polymorphonuclear leuokocytes (PMNs: Ly6C+Ly6G+), CD11c+ dendritic cells (Ly6C-Ly6G- CD11chi), monocytes (Ly6G-CD11c- CD11b+Ly6Chi) and macrophages (Ly6G- CD11c- CD11bhi Ly6Cint) determined using flow cytometry in (A) bone marrow, (B) lymph nodes and (C) spleen in...

M2 macrophage markers compared between WT M1vs. WT M0 and KO M1 vs. KO M0 macrophages. (XLSX)

Genes increased more than 2-fold in KO M1 vs. KO M0 macrophages. (XLSX)

miR-155 targets down-regulated in WT M1 vs. WT M0. (XLSX)

Classically (M1) and alternatively activated (M2) macrophages play distinct roles in various physiological and disease processes. M1 responses can cause inflammatory disease and tissue damage while M2 macrophages can limit inflammation and promote tissue repair. Therefore, understanding key players driving M1 or M2 phenotype may provide novel targe...

Pro-inflammatory T helper (Th) 1 and Th17 cell responses drive autoimmune attack of the central nervous system in Multiple Sclerosis (MS), resulting in disability. In contrast, regulatory Th2 and Treg responses are deficient. The reactivation and expansion of inflammatory T cells is linked to increased severity and active MS disease. Thus, therapeu...

View largeDownload slide Regulatory T cells (Tregs) are defective in multiple sclerosis. Severin et al . show that TGFβ signalling is reduced in T cells in multiple sclerosis owing to overexpression of miRNAs that negatively regulate the TGFβ pathway. This results in impaired Treg development, and implicates overexpression of specific miRNAs in mu...

Genetic studies suggest that the immune system is the greatest genetic contributor to multiple sclerosis (MS) susceptibility. Yet, these immune-related genes do not explain why inflammation is limited to the CNS in MS. We hypothesize that there is an underlying dysregulation in the CNS of MS patients that makes them more vulnerable to CNS inflammat...

Classically (M1) and alternatively activated (M2) macrophages exhibit distinct phenotypes and functions. It has been difficult to dissect macrophage phenotypes in vivo, where a spectrum of macrophage phenotypes exists, and also in vitro, where low or non-selective M2 marker protein expression is observed. To provide a foundation for the complexity...

Distinct M2 macrophage signature. IPA pathway analysis of genes more than 2FC up-regulated in M2 and more than 2FC down-regulated in M1 macrophages. Only genes identified by IPA analysis to be linked are pictured. Shaded genes represent genes followed up for further validation, as well as the main stimuli, mediators or markers of M2 phenotype. Arro...

Stability of the CD38+Egr2- (putative M1, A) and CD38-Egr2+ (putative M2, B) phenotype, determined by flow cytometry staining, from 24 hours to 6 days after differentiation of macrophages in M0, M1 or M2 conditions (n = 3–6 replicates from two independent experiments). (TIF)

Shared M1/M2 macrophage signature. IPA pathway analysis of common (more than 2FC) up-regulated (red) and down-regulated (green) genes in M1 and M2 macrophages compared to M0 macrophages. Only genes identified by IPA analysis to be linked are pictured. Arrows indicate direct interactions. Data shown are from the microarray shown in Figs 1 and 2. Gen...

Genes decreased more than 2-FC in M1 and M2 macrophages. (XLSX)

Categorization of M1 and M2 shared genes. (DOCX)

Distinct M1 macrophage signature. IPA pathway analysis of genes more than 2FC up-regulated in M1 while they were more than 2FC down-regulated in M2 macrophages. Only genes identified by IPA analysis to be linked are pictured. Shaded genes represent genes followed up for further validation, as well as the main stimuli, mediators or markers of M1 phe...

Genes increased more than 2-FC in both M1 and M2 macrophages. (XLS)

Background Recent studies suggest that innate immune responses may play a significant pathological role in systemic lupus erythematosus (SLE). TLR8 is an innate immune system receptor that stimulates inflammation by recognizing and binding to single-stranded viral RNA sequences, but recent work has shown that miR-21 can also act as an endogenous TL...

Pro-inflammatory (M1) macrophages are implicated in inflammatory diseases while pro-regenerative (M2) macrophages may be beneficial in Central Nervous System disorders. To modulate these phenotypes for therapeutic purposes, we need further understanding of the signaling pathways that define and distinguish M1 versus M2 macrophages. Here, we investi...

Multiple sclerosis (MS) is an immune-mediated demyelinating disease of the CNS. The disease is thought to be an autoimmune reaction mediated by autoreactive T cells. Interestingly, regulatory T cells (Tregs), protectors against autoimmune responses, are defective in MS patients. To better understand defects in the CD4 T cells of MS patients, a miRN...

Inhibition of methylation reactions suppresses T cell proliferation and inflammatory responses but the specific methylation enzyme target responsible for these effects is unknown. Protein Arginine Methyltranferases (PRMT), enzymes that catalyze dimethylation of arginine in histones and other proteins, have been proposed to mediate these effects. Am...

After spinal cord injury (SCI), “M1” (pro-inflammatory) and “M2” (anti-inflammatory) macrophages populate the site of injury. M1 macrophages are neurotoxic and hamper neuroregeneration while M2 macrophages have a pro-regenerative, anti-inflammatory phenotype. Therefore, therapeutic strategies that suppress M1 and enhance M2 macrophages after SCI ar...

Myeloid cells (MC) have potent immunoregulatory abilities that can be therapeutically useful to treat inflammatory disease. However, the factors which promote regulatory myeloid cell differentiation remain poorly understood. We have previously shown that estriol (E3) induces mature regulatory dendritic cells in vivo. To determine whether additional...

Multiple Sclerosis (MS) is an autoimmune, demyelinating disease of the central nervous system that can cause loss of motor function and is thought to result, in part, from chronic inflammation due to an antigen-specific T cell immune response. Current treatments suppress the immune system without antigen specificity, increasing the risks of cancer,...

Multiple sclerosis (MS) is an immune-mediated disease that results in destruction of the myelin sheath and axonal degeneration. Interestingly, while myelin-specific T cells are present in peripheral blood mononuclear cells (PBMC) of both healthy controls and MS patients, they only become pathogenic in MS patients. This suggests that some regulatory...

Th cell programming and function is tightly regulated by complex biological networks to prevent excessive inflammatory responses and autoimmune disease. The importance of microRNAs (miRNAs) in this process is highlighted by the preferential Th1 polarization of Dicer-deficient T cells that lack miRNAs. Using genetic knockouts, we demonstrate that lo...

Dimethyl fumarate (DMF) is an effective novel treatment for multiple sclerosis in clinical trials. A reduction of IFN-γ-producing CD4(+) T cells is observed in DMF-treated patients and may contribute to its clinical efficacy. However, the cellular and molecular mechanisms behind this clinical observation are unclear. In this study, we investigated...

Pro-inflammatory T cells mediate autoimmune demyelination in multiple sclerosis. However, the factors driving their development and multiple sclerosis susceptibility are incompletely understood. We investigated how micro-RNAs, newly described as post-transcriptional regulators of gene expression, contribute to pathogenic T-cell differentiation in m...

MicroRNAs (miRNAs) are small non-coding RNAs that regulate gene expression at the post-transcriptional level. miRNAs are highly expressed in cells of the immune and nervous system, attesting to their importance in Neuroimmunology. Besides their involvement in modulation of physiological and pathological processes, miRNAs hold high promise as diseas...

Effector Th1 cells perpetuate inflammatory damage in a number of autoimmune diseases, including MS and its animal model EAE. Recently, a self-regulatory mechanism was described in which effector Th1 cells produce the immunomodulatory cytokine IL-10 to dampen the inflammatory response in both normal and autoimmune inflammation. While the presence of...

Pro-inflammatory T cells mediate autoimmune demyelination in Multiple Sclerosis (MS). However, the factors driving their development and MS susceptibility are obscure. We investigated how miRNAs, newly described as post-transcriptional regulators of gene expression, contribute to pathogenic T cell differentiation in MS. We profiled miRNA expression...

Multiple sclerosis (MS) is an inflammatory disease of the central nervous system initiated by autoreactive CD4+ T cells of a T-helper (Th)1 and Th17 phenotype. Identifying novel factors that control Th differentiation will lead to a better understanding of MS pathogenesis and the development of new therapeutic strategies. MicroRNAs (miRs) are small...

Multiple sclerosis (MS) is an inflammatory disease of the central nervous system mediated by autoreactive CD4+ T cells of a Th1 and Th17 phenotype. Identifying novel factors that control Th differentiation will lead to a better understanding of disease pathogenesis and the development of new therapeutic strategies. MicroRNAs (miRs) are a class of s...

Arthritis is a prominent manifestation of Lyme disease, which is caused by infection with Borrelia burgdorferi (Bb). Chronic Lyme arthritis persisting even after antibiotic treatment is linked to HLA-DRB1*0401 (DR4) and related alleles. In contrast, patients whose Lyme arthritis resolves within 3 months postinfection show an increased frequency of...