TY - JOUR
T1 - Blocking immune cell infiltration of the central nervous system to tame Neuroinflammation in Amyotrophic lateral sclerosis
AU - Garofalo, Stefano
AU - Cocozza, Germana
AU - Bernardini, Giovanni
AU - Savage, Julie
AU - Raspa, Marcello
AU - Aronica, Eleonora
AU - Tremblay, Marie-Eve
AU - Ransohoff, Richard M.
AU - Santoni, Angela
AU - Limatola, Cristina
N1 - Funding Information: This work was supported by AIRC 22,329 2018, ARISLA NKINALS 2019 to S.G.; PRIN 2017 20178L7WRS_001, AIRC 2019: IG-23010 to C.L. M.E.T. is a Tier II Canada Research Chair in Neurobiology of Aging and Cognition. ALS Stichting grant “The Dutch ALS Tissue Bank” (A.E.). Publisher Copyright: © 2022
PY - 2022/10/1
Y1 - 2022/10/1
N2 - Neuroinflammation is one of the main hallmarks of amyotrophic lateral sclerosis (ALS). Recently, peripheral immune cells were discovered as pivotal players that promptly participate in this process, speeding up neurodegeneration during progression of the disease. In particular, infiltrating T cells and natural killer cells release inflammatory cytokines that switch glial cells toward a pro-inflammatory/detrimental phenotype, and directly attack motor neurons with specific ligand-receptor signals. Here, we assessed the presence of lymphocytes in the spinal cord of sporadic ALS patients. Furthermore, we demonstrate that blocking the extravasation of immune cells in the central nervous system using Natalizumab (NAT), an antibody for the α4 integrin, reduces the level of interferon-γ in the spinal cord of ALS mouse models, such as the hSOD1G93A and TDP43A315T mice, modifying microglia and astrocytes phenotype, increasing motor neuron number and prolonging the survival time. Taken together, our results establish a central role for the immune cells as drivers of inflammation in ALS.
AB - Neuroinflammation is one of the main hallmarks of amyotrophic lateral sclerosis (ALS). Recently, peripheral immune cells were discovered as pivotal players that promptly participate in this process, speeding up neurodegeneration during progression of the disease. In particular, infiltrating T cells and natural killer cells release inflammatory cytokines that switch glial cells toward a pro-inflammatory/detrimental phenotype, and directly attack motor neurons with specific ligand-receptor signals. Here, we assessed the presence of lymphocytes in the spinal cord of sporadic ALS patients. Furthermore, we demonstrate that blocking the extravasation of immune cells in the central nervous system using Natalizumab (NAT), an antibody for the α4 integrin, reduces the level of interferon-γ in the spinal cord of ALS mouse models, such as the hSOD1G93A and TDP43A315T mice, modifying microglia and astrocytes phenotype, increasing motor neuron number and prolonging the survival time. Taken together, our results establish a central role for the immune cells as drivers of inflammation in ALS.
KW - Amyotrophic lateral sclerosis
KW - Astrocytes
KW - Immune cells
KW - Inflammation
KW - Microglia
UR - http://www.scopus.com/inward/record.url?scp=85132862278&partnerID=8YFLogxK
U2 - https://doi.org/10.1016/j.bbi.2022.06.004
DO - https://doi.org/10.1016/j.bbi.2022.06.004
M3 - Article
C2 - 35688338
SN - 0889-1591
VL - 105
SP - 1
EP - 14
JO - Brain, behavior, and immunity
JF - Brain, behavior, and immunity
ER -