Increased expression of cell cycle proteins, including the transcription factor E2F1, is observed in a variety of aging-associated neurodegenerative diseases. E2F1 modulates the G1-S phase transition of the cell cycle, apoptosis, and inflammation, and its upregulation in neurodegenerative diseases may contribute to pathology by promoting all of these processes, leading to neuronal dysfunction/death. Thus, reducing E2F1 levels in neurons may mitigate the progression of neurodegeneration. However, E2F1tm1/tm1 mice exhibit central nervous system (CNS) pathology, with contradictory studies suggesting that E2F1 loss impairs or improves memory as measured by novel object recognition assays. Given that neuronal and synaptic function are affected by inherent neuronal processes and that neuroimmune interactions are regulated by CNS-resident innate immune cells, specifically microglia, we generated a conditional floxed E2F1 mouse (E2F1fx/fx) to study cell-type specific roles of E2F1. We then developed a novel constitutive E2F1 knockout (E2F1-/-) mouse to 1) reevaluate E2F1-mediated CNS pathology and neurocognitive behaviors to confirm the presence of CNS-associated phenotypes in our E2F1-/- mouse and 2) characterize inflammatory mediator release from E2F1-/- macrophages in response to differing doses of lipopolysaccharide (LPS) with and without priming to acquire a better understanding of E2F1’s role in inflammation. We found that E2F1 loss in E2F1-/- mice did not cause some of the reported E2F1tm1/tm1-associated CNS and peripheral pathologies, while discovering a novel E2F1-/- related phenotype: megakaryocytic hyperplasia. We also found that E2F1-/- macrophages exhibited anti-inflammatory (reduced IL-6 and TNF-alpha release) and pro-inflammatory (increased CCL-2 release) responses dependent on LPS dose and priming condition. These results suggest that aspects of mouse model design may account for altered neuron/synapse health observed in E2F1tm1/tm1 mice which may not be dependent on E2F1 loss alone, and that E2F1 has beneficial and detrimental functions in inflammation depending on its roles in initiation and resolution of inflammation. Further exploration of E2F1’s role in neuronal health and neuroinflammatory response should provide insight into not only the cell-type specific therapeutic development for neurodegenerative diseases but also the novel roles of E2F1 in innate immune memory.