title: Cytokine and chemokine alterations in tissue, CSF, and plasma in early presymptomatic phase of experimental allergic encephalomyelitis (EAE), in a rat model of multiple sclerosis.
abstract: Experimental allergic encephalomyelitis (EAE) is the most commonly used experimental animal model for human multiple sclerosis (MS) that has been used so far to study the acute and remission-relapsing phases of the disease. Despite the vast literature on neuroinflammation onset and progression in EAE, important questions are still open regarding in particular the early asymptomatic phase between immunization and clinical onset.
  
  
  
  In this study, we performed a time-course investigation of neuroinflammation and demyelination biomarkers in the spinal cord (SC), cerebrospinal fluid (CSF), and blood in EAE induced in dark agouti (DA) female rats compared to the controls and adjuvant-injected rats, using high-throughput technologies for gene expression and protein assays and focusing on the time-course between immunization, clinical onset (1, 5, 8 days post-immunization (DPI)), and progression (11 and 18 DPI). The expression profile of 84 genes related to T cell activation/signaling, adaptive immunity, cytokine/chemokine inflammation, demyelination, and cellular stress were analyzed in the tissue; 24 cytokines were measured in the CSF and plasma.
  
  
  
  The macrophage colony-stimulating factor (CSF1) was the first up-regulated protein as far as 1 DPI, not only in blood but also in CSF and SC. A treatment with GW2580, a selective CSF1R inhibitor, slowed the disease progression, significantly reduced the severity, and prevented the relapse phase. Moreover, both pro-inflammatory (IL-1β, TNF-α) and anti-inflammatory cytokines (IL-5, IL-10, VEGF) were up-regulated starting from 8 DPI. Myelin genes were down-regulated starting from 8 DPI, especially MAL, MBP, and PMP22 while an opposite expression profile was observed for inflammation-related genes, such as CXCL11 and CXCL10.
  
  
  
  This early cytokine and chemokine regulation indicates that novel biomarkers and therapeutic options could be explored in the asymptomatic phase of EAE. Overall, our findings provide clear evidence that CSF1R signaling regulates inflammation in EAE, supporting therapeutic targeting of CSF1R in MS.
authors.affiliation: Research and Development, Chiesi Farmaceutici S.p.A, Via Palermo 26/A, Parma, 43100, Italy. n.borjini@chiesi.com.|Health Science and Technologies Interdepartmental Center for Industrial Research (HST-ICIR), University of Bologna, Via Tolara di Sopra 41/E, Bologna, Ozzano Emilia I, 40064, Italy. n.borjini@chiesi.com.|IRET Foundation, Via Tolara di Sopra 41/E, Bologna, Ozzano Emilia, 40064, Italy. n.borjini@chiesi.com.
authors.forename: Nozha
authors.identifier: 0000-0003-3729-2521
authors.initials: N
authors.lastname: Borjini
authors.affiliation: Department of Pharmacy and Biotechnology, University of Bologna, Via Tolara di Sopra 41/E, Bologna, Ozzano Emilia, 40064, Italy.
authors.forename: Mercedes
authors.initials: M
authors.lastname: Fernández
authors.affiliation: Health Science and Technologies Interdepartmental Center for Industrial Research (HST-ICIR), University of Bologna, Via Tolara di Sopra 41/E, Bologna, Ozzano Emilia I, 40064, Italy.|IRET Foundation, Via Tolara di Sopra 41/E, Bologna, Ozzano Emilia, 40064, Italy.|Department of Veterinary Medical Sciences, University of Bologna, Via Tolara di Sopra 50, Ozzano Emilia, BO, 40064, Italy.
authors.forename: Luciana
authors.initials: L
authors.lastname: Giardino
authors.affiliation: Health Science and Technologies Interdepartmental Center for Industrial Research (HST-ICIR), University of Bologna, Via Tolara di Sopra 41/E, Bologna, Ozzano Emilia I, 40064, Italy.|IRET Foundation, Via Tolara di Sopra 41/E, Bologna, Ozzano Emilia, 40064, Italy.|Department of Pharmacy and Biotechnology, University of Bologna, Via Tolara di Sopra 41/E, Bologna, Ozzano Emilia, 40064, Italy.
authors.forename: Laura
authors.initials: L
authors.lastname: Calzà
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D000840:Anisoles / Q000627:therapeutic use; D016207:Cytokines / Q000097:blood / Q000134:cerebrospinal fluid / Q000235:genetics / Q000378:metabolism*; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology*; D004791:Enzyme Inhibitors / Q000627:therapeutic use; D005260:Female; D005620:Freund's Adjuvant / Q000633:toxicity; D006168:Guinea Pigs; D060066:Protein Interaction Maps / Q000502:physiology; D011743:Pyrimidines / Q000627:therapeutic use; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D016187:Receptors, Granulocyte-Macrophage Colony-Stimulating Factor / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology; D013116:Spinal Cord / Q000276:immunology / Q000378:metabolism; D013997:Time Factors
chemical_list: C506269:5-(3-methoxy-4-((4-methoxybenzyl)oxy)benzyl)pyrimidine-2,4-diamine; D000840:Anisoles; D016207:Cytokines; D004791:Enzyme Inhibitors; D011743:Pyrimidines; D012333:RNA, Messenger; D016187:Receptors, Granulocyte-Macrophage Colony-Stimulating Factor; D005620:Freund's Adjuvant
keywords: Biomarkers; CSF1; Experimental allergic encephalomyelitis; Multiple sclerosis; Neuroinflammation; Plasma