HomeENGLISH MAGAZINEMultiple sclerosis: trendy lymphocytes make way, neutrophils show face

Multiple sclerosis: trendy lymphocytes make way, neutrophils show face

Multiple sclerosis is an autoimmune disease that damages the insulating sheaths of nerve cells of the central nervous system, best known as myelin. People with the disease can lose vision, suffer weak limbs, show degenerative symptoms and exhibit impaired cognition. While multiple sclerosis has 17 approved therapies to modify the disease, none is able to halt disease progression. Thus, researchers use a mouse model called experimental autoimmune encephalomyelitis, or EAE, to discover disease mechanisms that may translate into treatments for patients with multiple sclerosis. Researchers at the University of Alabama at Birmingham now report in the journal JCI Insight how dysregulated neutrophils cause damage in a severe, mouse model form of EAE called atypical EAE, which attacks cerebellum brain tissue. Drs. Etty Benveniste, PhD, and Hongwei Qin, PhD, senior authors believe that these findings contribute to our understanding of the pathobiology of brain-targeted EAE and document the detrimental role of neutrophils in autoimmune neuro-inflammation. Benveniste and Qin are professor and associate professor in the UAB Department of Cell, Developmental and Integrative Biology.

Much evidence from neutrophils points to their detrimental impact in multiple sclerosis. Neutrophils are the most common white blood cells in the body, but their exact function in multiple sclerosis is unclear. Their normal, healthy function is to protect humans, as neutrophils speed to sites of infection or inflammation, aided by their ability to crawl out of the bloodstream and into affected tissues. In everyday life, people encounter them as the most prevalent cells found in pus, as an infection clears. Several strands of evidence from previous studies at UAB and elsewhere formed the groundwork for this current study. These include 1) UAB researchers and others have shown that brain-targeted, atypical EAE is predominantly a neutrophil-driven disease; 2) dysregulation of a cell-signaling pathway called JAK/STAT is associated with multiple sclerosis and EAE; and 3) a cytokine called granulocyte colony-stimulating factor (G-CSF) is known to have a detrimental role in multiple sclerosis, as it correlates with neurological disability and lesion burden in patients. In their experiments, the UAB researchers artificially dysregulated the JAK/STAT signaling system by using mice with a deleted Socs3 gene.

Socs3 is a negative regulator of the JAK/STAT pathway; in the absence of Socs3, the JAK/STAT pathway is overly active and promotes inflammation. As a result, mice with Socs3 deletion in their myeloid cells have a severe, brain-targeted, atypical form of EAE that is associated with cerebellar neutrophil infiltration and over-activation of STAT3, one of the seven STAT proteins that function in the JAK/STAT cell signaling pathway. Using this model, the researchers found that neutrophils from the cerebellum of mice lacking Socs3 showed a hyper-activated phenotype and produced excessive amounts of reactive oxygen species (ROS), that can damage cell structures. However, if mice were given compounds to neutralize ROS, the onset of atypical EAE was delayed and disease severity was reduced. The mechanisms causing these changes were an enhanced STAT3 activation in Socs3-deficient neutrophils, a hyper-activated phenotype in response to G-CSF, and an increased production of ROS after neutrophil priming by this cytokine. Furthermore, when compounds were given to mice to neutralize granulocyte colony-stimulating factor, the incidence and severity of atypical EAE was significantly reduced.

The researchers also sequenced messenger RNA in the Socs3-deficient neutrophils after stimulation by granulocyte colony-stimulating factor to identify the cell-signaling pathways and proteins that were most differentially affected. The RNA-Seq data also demonstrate that the STAT5 pathway, activated by GM-CSF, is enhanced in Socs3-deficient neutrophils after an 8-hour stimulation with G-CSF. Priming with this cytokine also rendered Socs3-deficient neutrophils more sensitive to GM-CSF treatment for ROS production. Another interesting finding from RNA sequencing is that neutrophils undergo metabolic changes in response to G-CSF, specifically increased glucose utilization and reduced oxidative activity in mitochondria. Drs Qin and Benveniste concluded: “Overall, our work elucidates that hypersensitivity of G-CSF/STAT3 signaling in Socs3-deficient mice leads to atypical EAE by enhanced neutrophil activation and increased oxidative stress, which may explain the detrimental role of this cytokine in multiple sclerosis patients. Furthermore, the work suggests that both granulocyte colony-stimulating factor and neutrophils may be therapeutic targets in MS”.

  • Edited by Dr. Gianfrancesco Cormaci, PhD, specialist in Clinical Biochemistry.

Scientific references

Yan Z et al., Qin H, Benveniste EN. JCI Insight 2019 Apr 2.

Woodberry T et al., Brüstle A. J Clin Med. 2018 Dec; 7(12).

Whittaker Hawkins RF et al. JCI Insight. 2017 Dec 7; 2(23). 

Rumble JM et al. J Exp Med. 2015 Jan 12; 212(1):23-35.

Dott. Gianfrancesco Cormaci
- Laurea in Medicina e Chirurgia nel 1998 (MD Degree in 1998) - Specialista in Biochimica Clinica nel 2002 (Clinical Biochemistry residency in 2002) - Dottorato in Neurobiologia nel 2006 (Neurobiology PhD in 2006) - Ha soggiornato negli Stati Uniti, Baltimora (MD) come ricercatore alle dipendenze del National Institute on Drug Abuse (NIDA/NIH) e poi alla Johns Hopkins University, dal 2004 al 2008. - Dal 2009 si occupa di Medicina personalizzata. - Guardia medica presso strutture private dal 2010 - Detentore di due brevetti sulla preparazione di prodotti gluten-free a partire da regolare farina di frumento immunologicamente neutralizzata (owner of patents concerning the production of bakery gluten-free products, starting from regular wheat flour). - Responsabile del reparto Ricerca e Sviluppo per la società CoFood s.r.l. (leader of the R&D for the partnership CoFood s.r.l.) - Autore di un libro riguardante la salute e l'alimentazione, con approfondimenti su come questa condizioni tutti i sistemi corporei. - Autore di articoli su informazione medica e salute sui siti web salutesicilia.com, medicomunicare.it e in lingua inglese sul sito www.medicomunicare.com
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