Mef2C restrains microglial inflammatory response and is lost in brain ageing in an IFN-I-dependent manner
Aleksandra Deczkowska1, Orit Matcovitch-Natan1,2, Afroditi Tsitsou-Kampeli1
1Department of Neurobiology, Weizmann Institute of Science, Rehovot, 7610001, Israel.
Abstract:
During ageing, microglia acquire a phenotype that may negatively affect brain function. Here we show that ageing microglial phenotype is largely imposed by interferon type I (IFN-I) chronically present in aged brain milieu. Overexpression of IFN-β in the CNS of adult wild-type mice, but not of mice lacking IFN-I receptor on their microglia, induces an ageing-like transcriptional microglial signature, and impairs cognitive performance. Furthermore, we demonstrate that age-related IFN-I milieu downregulates microglial myocyte-specific enhancer factor 2C (Mef2C). Immune challenge in mice lacking Mef2C in microglia results in an exaggerated microglial response and has an adverse effect on mice behaviour. Overall, our data indicate that the chronic presence of IFN-I in the brain microenvironment, which negatively affects cognitive function, is mediated via modulation of microglial activity. These findings may shed new light on other neurological conditions characterized by elevated IFN-I signalling in the brain.Microglia cells in the brain regulate immune responses, but in ageing can negatively affect brain function. Here the authors show that the chronic presence of type I interferon in aged mouse brain impedes cognitive ability by altering microglia transcriptome and limiting Mef2C, a microglia 'off' signal.
Insights
Chronic brain interferon type I (IFN-I) drives microglial aging and cognitive decline. This IFN-I signaling downregulates Mef2C, a key microglial regulator, exacerbating immune responses and impairing brain function.
Area of Science:
- Neuroscience
- Immunology
- Aging Research
Background:
- Microglia, the brain's immune cells, adopt a detrimental phenotype during aging.
- This aging-associated microglial dysfunction can negatively impact overall brain function and cognitive abilities.
Purpose of the Study:
- To investigate the role of chronic interferon type I (IFN-I) in driving the aged microglial phenotype.
- To elucidate the molecular mechanisms by which IFN-I affects microglial function and cognitive performance.
Main Methods:
- Overexpression of IFN-β in the central nervous system (CNS) of adult wild-type mice.
- Utilizing mice lacking the IFN-I receptor specifically on microglia.
- Assessing microglial transcriptional signatures and cognitive performance.
- Investigating the regulation of myocyte-specific enhancer factor 2C (Mef2C) by IFN-I.
- Conducting immune challenges in mice with altered Mef2C expression in microglia.
Main Results:
- Chronic IFN-I in the aged brain milieu induces an aging-like microglial transcriptional signature.
- IFN-I overexpression impairs cognitive performance in wild-type mice, an effect not observed in mice lacking microglial IFN-I receptors.
- Age-related IFN-I downregulates Mef2C expression in microglia.
- Mice lacking Mef2C in microglia exhibit exaggerated responses to immune challenges and adverse behavioral outcomes.
Conclusions:
- The chronic presence of IFN-I in the aged brain microenvironment is a primary driver of detrimental microglial phenotypes and cognitive decline.
- IFN-I mediates its effects, in part, by downregulating Mef2C, a critical inhibitory signal in microglia.
- These findings offer insights into neurological conditions associated with elevated brain IFN-I signaling.
