The number of individuals affected by neurodegenerative diseases is increasing with our aging population. Age-dependent neuroinflammation is one contributing factor. Microglia are innate immune cells that maintain the health of neurons, but can also drive neuroinflammation. The aging process may alter the brain microenvironment thereby changing the phenotype of microglial cells and promoting the development of neuroinflammation. Aging and neuroinflammatory disease are associated with a reduction in stiffness of the brain. Microglia may detect changes in brain stiffness through mechanosensing, detection of physical forces transmitted by surrounding environment, and alter their function. Therefore, I hypothesize that the decrease in substrate stiffness, mimicking the reduced brain stiffness, promotes inflammatory microglial cell development. I used an in vitro model system to grow microglial cells on surfaces with different modulus of elasticity that mimic the normal or diseased brain environment. I found that microglial cells produced more proinflammatory cytokines with reduction in stiffness. Rho-associated protein kinase did not play a role in the regulation of inflammatory cytokine production. Phagocytosis of microbial particles increased with decreasing stiffness. Additionally, microglial cells adopted an activated amoeboid morphology on softer substrates. Finally, no difference in expression levels of antigen presentation receptors was observed. Overall, my studies show that microglial cells may undergo a proinflammatory shift upon exposure to decreased surface stiffness. My studies lay the foundation for considering therapeutically targeting the mechanistic pathway that microglial cells use to sense the environment.