Neuroinflammation

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Key concepts in ALS

Wikipedia

• Neuroinflammation is inflammation of the nervous tissue.
• It may be initiated in response to a variety of cues:
  • Toxic metabolites
  • Autoimmunity
  • Aging
  • Infection
    • Microbes
    • Viruses
  • Traumatic brain injury
  • Air pollution
  • Passive smoke
• In the central nervous system (CNS), including the brain and spinal cord, microglia are the resident innate immune cells that are activated in response to these cues.
• The CNS is typically an immunologically privileged site because peripheral immune cells are generally blocked by the blood–brain barrier (BBB), a specialized structure composed of astrocytes and endothelial cells.
• However, circulating peripheral immune cells may surpass a compromised BBB and encounter neurons and glial cells expressing major histocompatibility complex molecules, perpetuating the immune response.
• Although the response is initiated to protect the CNS from the infectious agent, the effect may be toxic and widespread inflammation as well as further migration of leukocytes through the BBB.

Neuroinflammation and ALS

Neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, ALS, and frontotemporal lobar dementia are among the most pressing problems of developed societies with aging populations. Neurons carry out essential functions such as signal transmission and network integration in the central nervous system and are the main targets of neurodegenerative disease. In this Review, I address how the neuron's environment also contributes to neurodegeneration. Maintaining an optimal milieu for neuronal function rests with supportive cells termed glia and the blood-brain barrier. Accumulating evidence suggests that neurodegeneration occurs in part because the environment is affected during disease in a cascade of processes collectively termed neuroinflammation. These observations indicate that therapies targeting glial cells might provide benefit for those afflicted by neurodegenerative disorders.

Dysregulated microglial responses are central in neurodegenerative proteinopathies, including amyotrophic lateral sclerosis (ALS) and frontotemporal lobar disease (FTLD). Pathologic TDP-43, which is typically found in intracellular inclusions, is a misfolding protein with emerging roles in ALS and FTLD. Recently, TDP-43 species have been found in extracellular fluids of patients; however, the overall implications of TDP-43-mediated signaling linked to neuroinflammation are poorly understood. Our work-the first, to our knowledge, to focus on innate immunity responses to TDP-43 aggregates-shows that such species are internalized by microglia and cause abnormal mobilization of endogenous TDP-43. Exposure to TDP-43 aggregates elicited not only IL-1β, but also NLRP3-dependent and noncanonical IL-18 processing. Moreover, we report a link between TDP-43 and neuronal loss via the apoptosis-independent emerging roles of caspase-3 in neurotoxic inflammation. Our results further support the view of noncell autonomous neurodegenerative mechanisms in ALS. Remarkably, we demonstrate that TDP-43 aggregates bind to and colocalize with MAPK/MAK/MRK overlapping kinase (MOK) and show that its phosphorylation status is disrupted. Finally, we show that this TDP-43-caused activation state can be altered by exogenous Hsp27 and Hsp70 chaperones. Our study provides new insight into the immune phenotype, mechanisms, and signaling pathways that operate in microglial neurotoxic activation in ALS.-Leal-Lasarte, M. M., Franco, J. M., Labrador-Garrido, A., Pozo, D., Roodveldt, C. Extracellular TDP-43 aggregates target MAPK/MAK/MRK overlapping kinase (MOK) and trigger caspase-3/IL-18 signaling in microglia.