Work

Microglial tunneling nanotubes restrain microglial activation induced by methamphetamine

Year: 2026

Type: article

Abstract: Microglia, the resident immune cells of the central nervous system (CNS), act as key sentinels in immune surveillance and mediate critical neuroimmune responses to pathological stimuli, including psychostimulants. Methamphetamine (METH), a widely abused psychostimulant, is known to induce neurotoxicity; however, the cellular mechanisms governing microglial adaptation to METH exposure remain largely elusive. Here, we show that microglia are highly sensitive to METH-induced stress, as short-term moderate METH exposure rapidly triggers microglial activation. However, these activated microglia do not exhibit robust pro-inflammatory cytokine induction, but instead display intracellular stress characterized by mildly reduced mitochondrial membrane potential together with cytosolic accumulation and aggregation of mitochondrial DNA (mtDNA). Mechanistically, METH exposure promotes the formation of homotypic tunneling nanotubes (TNTs) between microglia, likely through actin cytoskeleton remodeling and activation of cGAS-STING signaling. These TNTs may serve as conduits for intercellular mitochondrial transfer, thereby preserving cellular homeostasis. Conversely, pharmacological blockade of TNTs disrupts microglial homeostasis, enhances pro-inflammatory cytokine production, and ultimately alters METH-associated neurobehavioral response. Collectively, our findings identify TNT formation as a stress-induced adaptive mechanism that restrains excessive microglial activation in response to METH, providing novel insights into the regulation of microglial homeostasis under pathological insults.

Source: Journal of Neuroinflammation

DOI: 10.1186/s12974-026-04027-3