HMC3: rewriting the rules of microglial plasticity

Lucia Buccarello¹Anna Privitera²Konstantinos Partsinevelos³Karolina Serwa⁴Giuseppe Carota³Lucia Di Pietro³Vincenzo Cardaci⁵Renata Mangione¹Jay Sibbitts⁶Giuseppe Lazzarino⁷Angela Maria Amorini³Francesco Bellia³Valentina Di Pietro⁸Romana Jarosova⁹Fabio Di Domenico¹⁰BARBARA TAVAZZI¹Emiliano Maiani¹Giacomo Lazzarino¹Giuseppe Caruso^1,11*

• ¹Saint Camillus International University of Health and Medical Sciences, Rome, Italy
• ²Universita degli Studi di Catania Dipartimento di Scienze del Farmaco e della Salute, Catania, Italy
• ³Universita degli Studi di Catania Dipartimento di Scienze biomediche e biotecnologiche, Catania, Italy
• ⁴Uniwersytet Jagiellonski w Krakowie Wydzial Farmaceutyczny, Kraków, Poland
• ⁵Universita Vita Salute San Raffaele, Milan, Italy
• ⁶Department of Physical Sciences, Truman State University, Kirksville, United States
• ⁷LTA Biotech S.r.l., Catania, Italy
• ⁸University of Birmingham Department of Inflammation and Ageing, Birmingham, United Kingdom
• ⁹Department of Chemistry, Colorado State University, Fort Collins, United States
• ¹⁰Department of Biochemical Sciences, Universita degli Studi di Roma La Sapienza, Rome, Italy
• ¹¹IRCCS Ospedale San Camillo, Venice, Italy

Microglia are a key driver of neurodegenerative disease, orchestrating inflammatory signaling, metabolic stress responses, synaptic remodeling, and neuronal fate within the central nervous system (CNS). Among experimental models, the human HMC3 microglial cell line, HMC3, is one of the most widely used platforms models for mechanistic investigation and pharmacological screening of microglial dysfunction, particularly in neurodegenerative contexts. Nevertheless, a key question HMC3: rewriting the rules of microglial plasticity remains: how faithfully does HMC3 reflect human microglial biology? This review integrates current evidence on HMC3 cells, including their molecular and metabolic features, functional plasticity, and disease-oriented applications. HMC3 cells reproduce hallmark neurodegeneration-associated programs, such as stimulus-dependent polarization, oxidative and endoplasmic reticulum stress signaling, inflammasome activation, autophagy dysregulation, lipid remodeling, angiogenic cross-talk, and phagocytic clearance of amyloid and apoptotic debris, modeling processes relevant to Alzheimer's disease, Parkinson's disease, ischemic injury, and metabolic neurodegeneration. Neuron-microglia co-culture systems further demonstrate the direct impacts of HMC3 activation states on neuronal vulnerability and survival. We also summarize the expanding repertoire of pharmacological and genetic interventions applied to HMC3, highlighting their compatibility with high-throughput and multi-omics discovery platforms. Despite inherent limitations of immortalized models, HMC3 represents a powerful front-line tool for dissecting neurodegenerative microglial mechanisms and steering early therapeutic discovery.