NEUROPROTECTIVE IMMUNITY: Leukaemia Inhibitory Factor (LIF) as guardian of brain health

The immune system naturally protects the brain, exerting a key role in brain health including as a source of neurotrophic factors released by T lymphocytes (Filiano et al., 2017). But a fine line exists, qualified by inflammation, and the growing global epidemic of dementia is linked to inflammatory brain disease – coined “inflammaging”. Here normal neuro-protective immunity becomes suppressed in favour of chronic inflammatory immunity (Metcalfe et al., 2017). Key questions arise: can neuro-protective immunity be preserved during aging? Is inflammaging reversible? If yes, how can recovery be favoured? Some answers come from newly recognised regulatory valves in immunity, providing rheostats for cytokine receptor plasticity and revealing master switches accessible to therapeutic modulation: these endogenous switch mechanisms operate to control immune phenotype. Supported by data at the single cell level (Wilmes et al., 2015; Giese et al., 2005) the concept of receptor rheostats is linked to ubiquitin-mediated regulation: namely USP18 acting on interferon IFNα2/IFNβ signalling in innate immunity (Wilmes et al., 2015) and the RINGv E3-ligase RNF177 - known as “MARCH7” - regulating the LIF/IL-6 signalling axis in adaptive immunity (Gao et al., 2009). Overall, for therapy, the need is to target inappropriate inflammation, be it innate immunity or adaptive immunity, and to break any vicious cycle of inflammatory cascade between the two.