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Heterogeneous induction of microglia M2a phenotype by central administration of interleukin-4
Giovanna Pepe1, Giorgia Calderazzi2, Marcella De Maglie3
1Center of Excellence on Neurodegenerative Diseases, Department of Pharmacological and Biomolecular Sciences, University of Milan, via Balzaretti, 9, 20133, Milan, Italy. giovanna.pepe@unimi.it.
Background:
Acquisition of the M1 or M2 phenotypes by microglia has been shown to occur during the development of pathological conditions, with M1 activation being widely involved in neurotoxicity in relation with the anatomical localization and the reactivity of subtypes of microglia cells. On the contrary, little is known on the ability of microglia to undergo M2 polarization by interleukin-4 (IL4), the typical M2a polarization signal for peripheral macrophages.
Methods:
Recombinant mouse IL4 was injected in the third cerebral ventricle of mice to induce brain alternative polarization. The mRNA levels of Fizz1, Arg1, and Ym1 genes, known to be up-regulated by IL4 in peripheral macrophages, together with additional polarization markers, were evaluated in the striatum and frontal cortex at different time intervals after central administration of IL4; in parallel, M2a protein expression was evaluated in tissue extracts and at the cellular level.
Results:
Our results show that the potency and temporal profile of IL4-mediated M2a gene induction vary depending on the gene analyzed and according to the specific brain area analyzed, with the striatum showing a reduced M2a response compared with the frontal cortex, as further substantiated by assays of polarization protein levels. Of notice, Fizz1 mRNA induction reached 100-fold level, underscoring the potency of this specific IL4 signaling pathway in the brain. In addition, immunochemistry assays demonstrated the localization of the M2 response specifically to microglia cells and, more interestingly, the existence of a subpopulation of microglia cells amenable to undergoing M2a polarization in the healthy mouse brain.
Conclusions:
These results show that the responsiveness of brain macrophages to centrally administered IL4 may vary depending on the gene and brain area analyzed, and that M2a polarization can be ascribed to a subpopulation of IL4-responsive microglia cells. The biochemical pathways that enable microglia to undergo M2a activation represent key aspects for understanding the physiopathology of neuroinflammation and for developing novel therapeutic and diagnostic agents.
Insights
Interleukin-4 (IL4) can induce M2a polarization in microglia, a subpopulation of brain macrophages. This response varies by brain region and gene, offering insights into neuroinflammation and potential therapies.
Area of Science:
- Neuroscience
- Immunology
- Cell Biology
Background:
- Microglia can adopt M1 or M2 phenotypes during disease.
- M1 activation is linked to neurotoxicity.
- The ability of microglia to undergo M2 polarization via IL4 is poorly understood.
Purpose of the Study:
- To investigate the induction of M2a polarization in the brain by IL4.
- To identify M2a polarization markers and responsive cell populations in the brain.
Main Methods:
- Recombinant mouse IL4 was administered into the third cerebral ventricle.
- mRNA levels of M2a markers (Fizz1, Arg1, Ym1) were measured in the striatum and frontal cortex.
- M2a protein expression was assessed at tissue and cellular levels.
Main Results:
- IL4 induced M2a gene expression in a gene- and brain region-dependent manner.
- The striatum showed a reduced M2a response compared to the frontal cortex.
- A subpopulation of microglia in the healthy brain was identified as responsive to IL4-induced M2a polarization.
Conclusions:
- Central IL4 administration induces M2a polarization in a subset of microglia.
- The responsiveness varies by gene and brain area.
- Understanding IL4-mediated M2a activation in microglia is crucial for neuroinflammation research and therapeutic development.
