Neonatal lipopolysaccharide administration causes long-term changes in mouse immunosteroids

Early-life infections have enduring effects on the immune and endocrine systems. Glucocorticoids (GCs) are produced by the adrenal glands and also produced by lymphoid organs (immunosteroids). We investigated the impacts of early-life lipopolysaccharide (LPS) challenge on GC and mineralocorticoid regulation in blood and lymphoid organs. We administered saline vehicle (nVEH) or LPS (50 µg/kg body wt, ip) (nLPS) to neonatal mice on postnatal day (PND) 4 and 6 ("first hit"). We then administered saline vehicle (aVEH) or LPS (50 µg/kg body wt, ip) (aLPS) to adults on PND90 ("second hit"), in a 2 × 2 design. We collected whole blood, bone marrow, thymus, and spleen 4 h after treatment at PND90. We measured nine steroids via liquid chromatography-tandem mass spectrometry and measured transcripts of steroidogenic enzymes (Cyp11b1, Cyp11b2, Hsd11b1, and Hsd11b2), GC receptor, mineralocorticoid receptor, and hypothalamic-pituitary-adrenal axis components (Crh, Crhr1, Pomc, and Mc2r) via RT-qPCR. The nLPS treatment did not have significant effects on blood GC levels in adulthood. Nonetheless, nLPS treatment increased corticosterone and 11-dehydrocorticosterone levels in lymphoid organs of aLPS subjects. The nLPS treatment increased aldosterone levels in blood and bone marrow of aVEH females but decreased aldosterone levels in bone marrow and thymus of aVEH males. The nLPS treatment also increased transcripts for steroidogenic enzymes, especially the aldosterone-synthetic enzyme Cyp11b2, and modulated transcripts for steroid receptors, especially mineralocorticoid receptors, in lymphoid organs of aVEH and aLPS subjects. These findings suggest that elevated local GC and aldosterone production in lymphoid organs is a mechanism for the enduring effects of early-life infections on immune function.NEW & NOTEWORTHY Using a "two-hit" model in mice, we examined the effects of early-life lipopolysaccharide (LPS) administration on steroid regulation in blood and lymphoid organs. Mice received saline or LPS as neonates, and then saline or LPS as adults. Neonatal LPS heightened local glucocorticoid and systemic aldosterone responses to adult LPS treatment in bone marrow, thymus, and spleen. These data highlight the potential role of immunosteroids in developmental programming of immune function and health.