NIH Scientists Identify How Normally Protective Immune Responses Kill Neurons
National Institutes of Health (NIH) scientists studying inflammation of the brain have discovered why certain immune responses, which typically help cells recognize and fight viral and bacterial infections, can sometimes be harmful to the brain. Many brain disorders involve the death of neurons, or nerve cells, but how these neurons die is not well understood. A new study in The Journal of ImmunologyExternal Web Site Policy describes how the activation of normally protective immune responses causes nerve cells to die and identifies the protein responsible, providing a potential target for therapeutic intervention.
Researchers from NIH’s National Institute of Allergy and Infectious Diseases (NIAID) studied the effect of immune system proteins called toll-like receptors on neurons. These receptors detect infection by bacteria or viruses. They also can detect certain molecules released by dying neurons and associated with diseases such as Alzheimer’s. The researchers used a mouse model to study why stimulation of these receptors caused death in neurons, but not other cell types. They determined that toll-like receptors activated a protein called SARM1 in neurons, which induces their death by affecting the function of mitochondria, the cells’ energy producers.
The study builds on the NIAID group’s previous work showing that SARM1 also caused neuronal death during viral infections in the brain. The new research demonstrates that immune activation of neurons, even in the absence of viral infection, can cause them to die. By identifying SARM1 as a key molecule responsible for this process, researchers have an improved understanding of why the normally protective immune response can be detrimental when infection or damage occurs in the brain.
P. Mukherjee, et al. SARM1, not MyD88, mediates TLR7/TLR9-induced apoptosis in neurons. The Journal of ImmunologyExternal Web Site Policy DOI: 10.4049/jimmunol.1500953 (2015).
Karin Peterson, Ph.D., chief of the Neuroimmunology Unit in NIAID’s Laboratory of Persistent Viral Diseases, is available to comment on this study.
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http://www.jimmunol.org/content/early/2 ... 5d7178ad40
SARM1, Not MyD88, Mediates TLR7/TLR9-Induced Apoptosis in Neurons
Piyali Mukherjee*,1,2, Clayton W. Winkler*,1, Katherine G. Taylor*,1, Tyson A. Woods*, Vinod Nair†, Burhan A. Khan* and Karin E. Peterson*
- Author Affiliations
*Laboratory of Persistent Viral Diseases, Rocky Mountain Laboratories, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Hamilton, MT 59840; and
†Research Technologies Branch, Microscopy Unit, Rocky Mountain Laboratories, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Hamilton, MT 59840
- Author Notes
↵2 Current address: Department of Biological Sciences, Presidency University, Kolkata, West Bengal, India.
Address correspondence and reprint requests to Dr. Karin E. Peterson, Rocky Mountain Laboratories, National Institute of Allergy and Infectious Diseases, 903 South 4th Street, Hamilton, MT 59840. E-mail address: email@example.com
↵1 P.M., C.W.W., and K.G.T. contributed equally to this work.
Neuronal apoptosis is a key aspect of many different neurologic diseases, but the mechanisms remain unresolved. Recent studies have suggested a mechanism of innate immune-induced neuronal apoptosis through the stimulation of endosomal TLRs in neurons. TLRs are stimulated both by pathogen-associated molecular patterns as well as by damage-associated molecular patterns, including microRNAs released by damaged neurons. In the present study, we identified the mechanism responsible for TLR7/TLR9-mediated neuronal apoptosis. TLR-induced apoptosis required endosomal localization of TLRs but was independent of MyD88 signaling. Instead, apoptosis required the TLR adaptor molecule SARM1, which localized to the mitochondria following TLR activation and was associated with mitochondrial accumulation in neurites. Deficiency in SARM1 inhibited both mitochondrial accumulation in neurites and TLR-induced apoptosis. These studies identify a non–MyD88 pathway of TLR7/ TLR9 signaling in neurons and provide a mechanism for how innate immune responses in the CNS directly induce neuronal damage.
This work was supported by the Intramural Research Program of the National Institute of Allergy and Infectious Diseases.
Received April 24, 2015.
Accepted September 8, 2015.