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Remote hyperinflammation drives neurological disease via T-cell-mediated innate-like cytotoxicity

Cellular & Molecular Immunology volume 18, pages 1638–1640 (2021)Cite this article

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Inflammation is critical for the induction of immune responses to pathogens and other foreign substances. However, excessive local and systemic inflammation can have dire consequences beyond the original site of inflammation. A link between peripheral inflammation and neuropathology has been suggested for many diseases, including influenza infection, liver cirrhosis, and irritable bowel syndrome.1,2,3 Arguably, the vast majority of inflammatory diseases have been associated with deleterious neurological outcomes. Likewise, immunotherapies, such as CAR T-cell treatment, are known for their high risk of cytokine release syndrome and associated neurotoxicity. However, the mechanism behind this phenomenon of inflammation-induced neuropathology remains largely misunderstood. Preclinical evidence from animal models that accurately depict this phenomenon is limited; these models will be essential to uncover the role of peripheral inflammation in neurological complications of disease. Beginning to fill this gap in understanding, Zhou et al. reported critical evidence linking lymphocytes from the inflamed gut to neurological sequelae in infants with necrotizing enterocolitis (NEC).4 These results pave the way to understanding how peripheral inflammation can adversely enhance immune activation and result in downstream neurological disease.

NEC is a devastating gastrointestinal disease in premature infants that involves sudden necrosis of the intestines and results in death in >30% of cases. Gut inflammation, bacterial dysbiosis, and TLR4 activation in the intestinal epithelium have been demonstrated to play a role in the mechanism of severe NEC.5 Unfortunately, ~45% of survivors of NEC experience long-term consequences, including severe brain injury resulting in hearing, visual, psychomotor, and cognitive impairments.6 However, the connection between NEC and brain injury has remained elusive. Zhou et al. were the first to define the mechanism through which inflammation and necrosis of the gut lead to off-target neuropathology facilitated by CD4+ T cells in newborns with NEC. Critically, these results may not be limited to neonatal disease, but may be broadly applicable to neuroinflammatory disorders of varying origins.

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Fig. 1: Mechanisms of hyperinflammation-induced T cell activation and innate-like cytotoxicity.

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Acknowledgements

Elizabeth Balint is a recipient of the Frederick Banting and Charles Best Canada Graduate Scholarship-Master’s from the Canadian Institutes of Health Research. Ali Ashkar is also a recipient of a CIHR Tier 1 Canada Research Chair.

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  1. Department of Medicine, McMaster Immunology Research Centre, McMaster University, Hamilton, ON, Canada

    Elizabeth Balint & Ali A. Ashkar

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Correspondence to Ali A. Ashkar.

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Balint, E., Ashkar, A.A. Remote hyperinflammation drives neurological disease via T-cell-mediated innate-like cytotoxicity. Cell Mol Immunol 18, 1638–1640 (2021). https://doi.org/10.1038/s41423-021-00705-9

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