The Granulocytes may be key to treating incurable neurological diseases

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Research led by investigators at The Ohio State University Wexner Medical Center provides new hope for recovery from degenerative neurological diseases – such as ALS and multiple sclerosis – as well as from damage caused by traumatic brain and spine injuries and stroke.

Using a mouse model, researchers at Ohio State and the University of Michigan discovered a new type of immune cell that not only rescues damaged nerve cells from death, but partially reverses nerve fiber damage.

The research team also identified a human immune cell line, with similar characteristics, that promotes nervous system repair.

Study findings are published in the journal Nature Immunology.

“This immune cell subset secretes growth factors that enhance the survival of nerve cells following traumatic injury to the central nervous system.

It stimulates severed nerve fibers to regrow in the central nervous system, which is really unprecedented,” said Dr. Benjamin Segal, professor and chair of the Department of Neurology at The Ohio State College of Medicine and co-director of the Ohio State Wexner Medical Center’s Neurological Institute.

“In the future, this line of research might ultimately lead to the development of novel cell based therapies that restore lost neurological functions across a range of conditions.”

Research led by investigators at The Ohio State University Wexner Medical Center provides new hope for recovery from degenerative neurological diseases — such as ALS and multiple sclerosis — as well from as damage caused by traumatic brain and spine injuries and stroke. Credit: The Ohio State University Wexner Medical Center

The cell discovered by these researchers is a granulocyte, a type of white blood cell that has small granules.

The most common granulocytes, neutrophils, normally help the body fight off infection. The unique cell type resembles an immature neutrophil but is distinctive in possessing neuroprotective and neuroregenerative properties.

It drives central nervous system axon (nerve) regrowth in vivo, in part through the secretion of a cocktail of growth factors.

“We found that this pro-regenerative neutrophil promotes repair in the optic nerve and spinal cord, demonstrating its relevance across CNS compartments and neuronal populations.

A human cell line with characteristics of immature neutrophils also exhibited neuro-regenerative capacity, suggesting that our observations might be translatable to the clinic,” said first author Dr. Andrew Sas, an assistant professor and physician scientist in the Department of Neurology at Ohio State.

Researchers demonstrated the therapeutic potency of the immature neutrophils subset by injecting them into mice with crush injury to the optic nerve or lacerated nerve fibers in the spinal cord. Mice injected with the new neutrophil subset, but not more typical mature neutrophils, grew new nerve fibers.

“I treat patients who have permanent neurological deficits, and they have to deal with debilitating symptoms every day. The possibility of reversing those deficits and improving the quality of life of individuals with neurological disorders is very exciting,” said Dr. Segal, who’s also director of Ohio State’s Neuroscience Research Institute.

“There’s so much that we’re learning at the bench that has yet to be translated to the clinic, I think there’s huge potential for future medical breakthroughs in our field.”

The next step is to harness this cell and expand it in a lab to enhance its healing effects. Researchers hope these cells can then be injected into patients to improve function and mobility and slow or stop progressive neurological decline.

“Our findings could ultimately lead to the development of novel immunotherapies that reverse central nervous damage and restore lost neurological function across a spectrum of diseases,” Sas said.


Tridirectional communication linking the nervous, endocrine, and immune system has become an extensively investigated scientific area in recent years (1–3).

If this emerging pathophysiological concept is correct, immunological alterations may not be unique to one neurological disease but may extend to other diseases that also signal through pathways of this tridirectional communication. However, cross-study comparisons are limited, as time points of sample acquisition, assays used to determine the activation status, and determinants differ between studies.

Therefore, we here compare, with an identical approach regarding sample acquisition, assays, and cytokine profiles, the cellular and humoral immunological changes induced by two neurological conditions of different etiology, i.e., seizures and stroke.

Ischemic stroke promotes so-called excitotoxic neuronal death, leading to dramatic and often irreversible loss of function. Neuroinflammation lead by granulocytes and monocytes occurs within hours after stroke onset (4–7). Following seizures, cell death is much less dramatic but is also believed to be initiated by excitotoxicity (8).

Neuroinflammation is an important hallmark of epileptogenesis (9): Monocytes and granulocytes infiltrating the brain can be detected after seizures (10), and macrophages remain present in the hippocampus until chronic seizures develop in an experimental model (9). These central immunological consequences of seizures resemble findings of neuroinflammation subsequent to stroke.

Post-stroke immune alterations are thought to be induced by activation of the hypothalamic-pituitary axis (HPA) and its release of stress hormones (1, 11). Several studies have reported increased levels of epinephrine and norepinephrine or its stable metabolites metanephrine and normetanephrine after stroke (1).

Increased metanephrine and normetanephrine levels during the first days after stroke are associated with lymphopenia, subsequent infections, and increased 3-month mortality rate (12, 13).

In addition, the pro-inflammatory danger-associated molecular pattern (DAMP) High-Mobility-Group-Protein B1 (HMGB-1) is thought to play an important role in the modulation of post-stroke immune alterations (12, 14). HMGB-1 binds DNA within the nucleus but can be passively released during (brain) cell death or actively secreted by immune cells as an alarmin (15).

Post stroke the amount of HMGB-1 correlates rather with the amount of leukocytes in the peripheral blood than with the brain lesion size (9). Also, in epilepsy HMGB-1 is extensively discussed as an important mediator of neuroinflammation and as part of the pathophysiological mechanisms. However, our knowledge here is mainly based on animal models (16).

DAMPs are important regulators of the immune system after tissue injury and also include cell-free mitochondrial DNA (mtDNA). Release of mtDNA from the mitochondrium into the cytoplasm or into the extracellular milieu activates triggers various inflammatory pathways like inflammasome formation and cytokine production (17).

Recently, mtDNA was shown to contribute to systemic inflammatory response syndrome in trauma (18) and to be increased in cerebrospinal fluid (CSF) of children with traumatic brain injury (19). Its role in stroke and seizures has not been investigated.

In stroke patients profound peripheral immune alterations associated with stroke-induced infections can be detected. Main changes include lymphocytopenia, and reduced expression of Human Leukocyte Antigen—DR isotype (HLA-DR) on monocytes (20). HLA-DR is an MHC class II cell surface receptor which is responsible for the presentation of antigens to the immune system. Presentation leads to an induction or inhibition of T-cell responses depending on the provided costimulatory signals (21).

In seizures our knowledge about functional changes of immune cell subsets in the peripheral blood is scarce. Also, only very little is known about the impact of different seizure types. The level of white blood cells is elevated in patients immediately after complex partial (PS) and/or generalized tonic-clonic seizures (GTCS) (22). Sarkis et al. found higher leukocyte counts after GTCS compared to PS, predominantly due to the increased number of monocytes (10), which is comparable to changes shortly after stroke onset (20).

After stroke and after seizures, monocytes and granulocytes are the first cell types to invade the brain from the periphery after the event. Therefore, our study compares alterations of monocytes’ and granulocytes’ subpopulations within the peripheral blood in both groups of patients.

CD14 gets expressed by monocytes and macrophages and helps to detect pathogens by binding lipopolysaccharides (LPS) (23). CD16 is the FcγRIII-receptor and binds IgG loaded antigens and thus initiates antibody-dependent cell-mediated cytotoxicity.

Monocytes can be divided into three different cell subpopulations by their expression of CD14 and CD16: (i) classical (CD14++CD16−), (ii) intermediate (CD14++CD16+), and (iii) non-classical monocytes (CD14dimCD16+). Classical monocytes, as the main monocyte compartment (85% of circulating monocytes), were reported to differentiate into tissue macrophages and secrete different pro- and anti-inflammatory cytokines.

Intermediate (~5%) and non-classical monocytes (~10%) reveal different levels of phagocytosis and cytokine secretion, and are differentially expanded in certain diseases (24–26): While intermediate monocytes are described to produce IL-10 after LPS stimulation (27), non-classical monocytes are suggested to release tumor necrosis factor—α (TNF-α) in response to certain stimuli (23, 28).

Although the percentage of classical monocytes did not change after stroke, intermediate monocytes increased and non-classical monocytes were shown to be downregulated (29, 30).

Granulocytes have similarly been subdivided into three different subpopulations (31, 32): (i) The major granulocyte subset within the peripheral blood, referred to as “classical granulocytes” (CD16++CD62L+), expresses high levels of CD16 and to some degree CD62L—a cell adhesion molecule found on leukocytes (L-selectin), (ii) pro-inflammatory granulocytes are defined as CD16dimCD62L+ cells, and (iii) anti-inflammatory granulocytes as CD16++CD62L−.

Like classical monocytes, classical granulocytes develop into tissue homing granulocytes. Anti-inflammatory granulocytes display immune suppressive function after LPS stimulation and pro-inflammatory granulocytes are characterized by a high phagocytotic activity (31, 32).

In addition, the surface activation markers HLA-DR, CD32, CD62L, and CD11b were quantified on the three different subsets either monocytes or granulocytes. CD32 is a Fc receptor which mediates multiple cell-type specific functions including the release of inflammatory mediators (33) and phagocytosis (34).

CD11b plays a critical role in pathogen recognition and mediates adaptive immune responses, as well as cell adhesion, endocytosis and leukocyte migration (35). To our knowledge no data exist about the regulation of these monocyte and granulocyte subsets in stroke and after seizures.

The aim of this prospective study was to investigate the following immune-parameters in a cohort of patients with a seizure disorder immediately after the epileptic seizure compared to age-matched controls: the endocrine transmitters normetanephrine, metanephrine, and the humoral pro-inflammatory DAMPs HMGB-1 and mtDNA; changes of the adaptive immune system; classical, intermediate, and non-classical subsets of monocytes as well as pro-inflammatory, anti-inflammatory, and classical subsets of granulocytes.

To understand common and disease specific pathways of brain-immune-endocrine-interactions, we additionally compared the observed immune alterations induced by seizures to immune alterations found in patients after stroke. Stroke data were analyzed in regard to a second control cohort with age-matched healthy controls.

Furthermoree we investigated if the extent of immunologic alterations is determined by the occurring seizure type [complex partial (PS) and/or generalized tonic-clonic seizures (GTCS)].

reference link : https://www.frontiersin.org/articles/10.3389/fneur.2020.00425/full


More information: A new neutrophil subset promotes CNS neuron survival and axon regeneration, Nature Immunology (2020). DOI: 10.1038/s41590-020-00813-0 , www.nature.com/articles/s41590-020-00813-0

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