Natural killer cells of the immune system as an underlying cause of Amyotrophic Lateral Sclerosis

Three departments of Sapienza University of Rome have coordinated and collaborated in a new international study that proves, for the first time, the involvement of Natural Killer cells (NK) in the early stages of ALS. The study, published on Nature Communications journal, suggests a new possible therapeutic target for the development of specific therapies

Amyotrophic lateral sclerosis (ALS) is a rare neurodegenerative disease affecting, every year, 1 out of 300.000 individuals, leading to the progressive degeneration of motor neurons with denervation and atrophy of skeletal muscles. To date, an adequate cure able to prolong and significantly improve the patient's life does not exist.

In the past, as with other nervous system diseases, studies on ALS used to be neurocentric-oriented, with neuron considered the only explanation underlying the pathology. More recently, research has focussed its attention also on glia cells, a significant element of the nervous system, and on the immune system cells, proving that the inflammatory mechanisms play a key role in the development and progression of this and other neurodegenerative diseases.

A new international study, involving the Departments of Physiology and Pharmacology, Molecular Medicine and Human Neuroscience of Sapienza University, has proved how some immune system cells, called Natural Killer (NK) play a major role in the death of motor neurons and in the activation of the cytokine mechanism during ALS progression, by invading the central nervous system. The research is part of the project NKINALS (Natural Killer cells Interplay with motor Neurons and immune cells in Amyotrophic Lateral Sclerosis), funded by AriSLA (call for projects 2019).

The research outcomes, suggesting NK cells as new potential therapeutic target, have been published on Nature Communications journal.

By using two murine models of the disease and human tissue samples of ALS patients, researchers have observed how these peripheral immune cells already leak in the central nervous system in a presymptomatic phase, causing the death of motor neurons both in the motor areas of the cerebral cortex and in the spinal cord. More precisely, the neurotoxic action of NK cells is induced by the interaction with motor neurones (through proteins on their membrane) which are identified as cells to eliminate.

In addition to direct neurotoxic action, these cells are able to modulate the central nervous system microenvironment through the release of interferon gamma which changes the activity of microglia cells from “watchmen” of the nervous system to “accomplices” in the neuroinflammatory process.

“We have then demonstrated that by eliminating the NK cells or blocking the interferon gamma activity,” – says Cristina Limatola, coordinator of the Sapienza University team – “the inflammatory status of microglia can be reduced and the number of regulatory T cells that leak in the central nervous system, increased. The consequence is a slowdown in the onset of motor deficits in ALS and a longer survival threshold of the animals.”

The results of the study highlight the importance of finding a specific therapy aimed at modulating the motor neurons’ microenvironment to improve the patient's life, suggesting, in particular, the NK cells as a possible therapeutic target.

References:

Natural killer cells modulate motor neuron-immune cell cross talk in models of Amyotrophic Lateral Sclerosis - Stefano Garofalo, Germana Cocozza, Alessandra Porzia, Maurizio Inghilleri, Marcello Raspa, Ferdinando Scavizzi, Eleonora Aronica, Giovanni Bernardini, Ling Peng, Richard M. Ransohoff, Angela Santoni & Cristina Limatola - Nature Communicationsvolume 11, Article number: 1773 (2020) https://doi.org/10.1038/s41467-020-15644-8