Background <p>The immune system plays a pivotal role in progressing an injury through the healing cascade. However, comorbidities often lead to dysregulation of this response and are implicated in wound chronicity or stalling in the inflammatory phase, necessitating clinical intervention. The maternal-fetal interface, one of the most striking immunomodulatory microenvironments to be found in mammals, may be leveraged therapeutically in wound healing through the application of amniotic tissue allografts.</p> Methods <p>This study investigates the influence of dehydrated human amnion chorion membrane (DHACM) and lyophilized human amnion and chorion membrane (LHACM) on the inflammatory response of monocytes and macrophages in vitro. Human THP-1 monocytes and macrophages were challenged with lipopolysaccharide (LPS) or LPS + interferon gamma (INFγ), respectively, to model inflammatory conditions.</p> Results <p>LHACM and DHACM treatment significantly dampened inflammasome activity and pro-inflammatory protein production while enhancing cell survival in LPS-challenged monocytes. LPS/INFγ-challenged macrophages exhibited a phenotypic shift with treatment, synonymous with repair or regeneration functionality. This was further confirmed when these cells demonstrated corresponding attenuation of pro-inflammatory cytokine production, dampened inflammasome activity, and increased survival. Additionally, the rate of efferocytosis by DHACM and LHACM-treated macrophages was substantially elevated, indicating more efficient clearance of dead cell debris.</p> Conclusion <p>These results indicate that DHACM and LHACM modulate the pro-inflammatory response of monocytes and macrophages, while enhancing the pro-reparative functions including efferocytotic capacity and cell survival. These data are suggestive of a potential cellular mechanism by which DHACM and LHACM may facilitate an efficient and appropriate inflammatory response to support the progression through the healing cascade.</p>