TY - JOUR T1 - A potent myeloid response is rapidly activated in the lungs of premature Rhesus macaques exposed to intra-uterine inflammation JF - bioRxiv DO - 10.1101/2021.05.28.444219 SP - 2021.05.28.444219 AU - Courtney M. Jackson AU - Martin Demmert AU - Shibabrata Mukherjee AU - Travis Isaacs AU - Jerilyn Gray AU - Paranthaman Senthamaraikannan AU - Pietro Presicce AU - Kashish Chetal AU - Nathan Salomonis AU - Lisa A. Miller AU - Alan H. Jobe AU - Suhas G. Kallapur AU - William J. Zacharias AU - Ian P. Lewkowich AU - Hitesh Deshmukh AU - Claire A. Chougnet Y1 - 2021/01/01 UR - http://biorxiv.org/content/early/2021/05/29/2021.05.28.444219.abstract N2 - Intrauterine inflammation/infection (IUI), which is present in up to 40% of premature births, leads to elevated levels of pro-inflammatory mediators and microbial products within the amniotic fluid, which come in close contact to fetal mucosae. Yet, knowledge on the fetal mucosal responses to IUI exposure remains limited. To address these questions, we used a non-human primate model of IUI, in which pregnant Rhesus macaques received intra-amniotic (IA) LPS, compared with IA saline.We found that IA LPS exposure induced a robust and rapid inflammation of the fetal lung, but not the intestine. This inflammatory response was characterized by high levels of pro-inflammatory cytokines in the lung and the alveolar wash, and a potent myeloid cell response, dominated by neutrophils and monocytes/macrophages. scRNAseq analyses of fetal lungs showed that the infiltrating (neutrophils and inflammatory monocytes) and the resident (alveolar and interstitial macrophages) myeloid cells exhibited transcriptional profiles consistent with exposure to TLR ligands, as well as to cytokines, notably IL-1 and TNFα. However, blocking IL-1 signaling or TNFα, alone or simultaneously by administering inhibitors intra-amniotically and subcutaneously to the dam only partially blunted fetal lung inflammation.Together, our novel data indicate that the fetal innate immune system can mount a rapid multi-factorial mucosal innate response to IUI, responding both to direct signaling by bacterial products and to indirect cytokine-mediated pathways of activation. These data thus provide more mechanistic insights into the association between IUI exposure and the post-natal lung morbidities of the premature infant.Competing Interest StatementThe authors have declared no competing interest. ER -