Cool T, Baena A Rodriguez Y, Rommel Mge, Mattingly C, Bachinsky E, Saini S, Chattopadhyaya S, Manso B A, Rajendiran S, Worthington A K, Poscablo D M, Deguzman A, Berger-Cahn T, Boyd D F, Forsberg E C
Program in Biomedical Science and Engineering, University of California Santa Cruz, Santa Cruz, CA 95064, USA.
Institute for the Biology of Stem Cells, University of California Santa Cruz, Santa Cruz, CA 95064, USA.
bioRxiv. 2025 Feb 25:2025.02.23.639728. doi: 10.1101/2025.02.23.639728.
Tobacco use during pregnancy has many deleterious health consequences for not only the smoking mother, but also on the unborn fetus. Children of smoking mothers are reported to have higher frequency and severity of respiratory diseases later in life; however, the mechanisms driving this increased vulnerability are not clearly understood. One potential cause of increased disease susceptibility is an altered immune system, originating in epigenetically maladaptive hematopoietic stem cells (HSCs). Here, we show that perinatal nicotine exposure (PNE) alters the establishment of HSCs and fetal-derived non-traditional tissue immune cells, with no alterations in circulating immune cell numbers. Suppression of HSCs and lung immune cells persisted for weeks after PNE had ceased. Strikingly, PNE led to increased disease susceptibility and severity upon challenge with influenza A virus in adulthood. This was associated with significant and highly selective alterations in lung immune cells, emphasizing the importance of cellular mechanisms in resilience to infections. Together, these experiments demonstrate that perinatal exposures that have deleterious consequences on hematopoietic establishment can impair immune function for life and identify the cellular mechanisms by which perinatal nicotine exposure predisposes the offspring to a weakened defense against respiratory pathogens.
孕期吸烟不仅会给吸烟的母亲带来诸多有害的健康后果，还会影响未出生的胎儿。据报道，吸烟母亲的孩子在日后生活中患呼吸系统疾病的频率和严重程度更高；然而，导致这种易感性增加的机制尚不清楚。疾病易感性增加的一个潜在原因是免疫系统改变，其起源于表观遗传适应不良的造血干细胞（HSC）。在这里，我们表明围产期尼古丁暴露（PNE）会改变造血干细胞和胎儿来源的非传统组织免疫细胞的建立，而循环免疫细胞数量没有变化。PNE停止后，造血干细胞和肺免疫细胞的抑制持续了数周。引人注目的是，PNE导致成年后感染甲型流感病毒时疾病易感性和严重程度增加。这与肺免疫细胞的显著且高度选择性改变有关，强调了细胞机制在抵抗感染中的重要性。总之，这些实验表明，对造血建立有有害影响的围产期暴露会损害终身免疫功能，并确定了围产期尼古丁暴露使后代易患呼吸道病原体防御减弱的细胞机制。
