LAUSR

Preterm birth, the leading cause of neonatal morbidity and mortality worldwide, results from preterm labor, a syndrome that includes multiple etiologies. In this review, we have summarized the immune mechanisms implicated in intra-amniotic inflammation, the best-characterized cause of preterm labor and birth. While the intra-amniotic inflammatory responses driven by microbes (infection) or alarmins (sterile) have some overlap in the participating cellular and molecular processes, the distinct natures of these two conditions necessitate the implementation of specific approaches to prevent adverse pregnancy and neonatal outcomes. Intra-amniotic infection can be treated using the correct antibiotics, whereas sterile intra-amniotic inflammation could potentially be treated using a combination of anti-inflammatory drugs (e.g., betamethasone, inflammasome inhibitors, etc.). Recent evidence also supports a role for fetal T-cell activation as a newly described trigger for preterm labor and birth in a subset of cases. Moreover, here we also provide evidence of two potential immune mechanisms responsible for a subset of preterm births formerly considered to be idiopathic. First, the impairment of maternal Tregs can lead to preterm birth, likely due to the loss of immunosuppressive activity resulting in unleashed effector T-cell responses. Second, homeostatic macrophages were shown to be essential for maintaining pregnancy and promoting fetal development, and the adoptive transfer of homeostatic M2-polarized macrophages shows great promise for preventing inflammation-induced preterm birth. Collectively, in this review, we discuss established and novel immune mechanisms responsible for preterm birth and highlight potential targets for novel strategies aimed at preventing the multi-etiological syndrome of preterm labor.