Microglial activation and RAS signaling: a dual-edged sword in neuroinflammation

Microglia, the resident immune cells of the central nervous system (CNS), play a pivotal role in monitoring neuronal activity, maintaining tissue homeostasis, and orchestrating immune responses. Under physiological conditions, microglia support neuronal survival and synaptic remodeling, in part through anti-inflammatory mechanisms and clearance of cellular debris. However, dysregulated microglial activation is implicated in a wide variety of pathologic states, including neurodegenerative diseases, stroke, and hypertension, largely through the induction of chronic neuroinflammation. Emerging evidence highlights the renin-angiotensin system (RAS) as a critical modulator of microglial activity. Microglia express most RAS components, including angiotensinogen, angiotensin-converting enzyme (ACE), ACE2, angiotensin II type 1 (AT₁R) and type 2 (AT₂R) receptors, and Mas1 receptor (Mas1R), enabling local generation of angiotensin peptides and autocrine/paracrine signaling. Activation of AT₁R leads toward proinflammatory reactive microglial phenotypes, characterized by elevated release of cytokines and reactive oxygen species, whereas AT₂R and Mas1R signaling transitions toward more homeostatic anti-inflammatory phenotypes, supporting tissue repair and neuronal protection. Dysregulation of this balance contributes to chronic neuroinflammation and may impact autonomic nervous system activity, linking microglial RAS signaling to systemic homeostatic alterations. Here, we review current literature into the expression, regulation, and functional consequences of RAS components in microglia, highlighting each element expression and signaling as regulators of neuroimmune activity while attempting to move away from the outdated M1/M2 nomenclature. We also discuss the therapeutic potential of pharmacologically targeting microglial RAS to shift reactive microglia toward a more homeostatic state, offering a promising strategy to mitigate neuroinflammation and protect against neurodegenerative and cardiovascular pathologies. Collectively, understanding the microglial RAS provides new avenues for intervention in CNS diseases associated with chronic inflammation.