Progesterone Attenuates Brain Inflammatory Response and Inflammation-Induced Increase in Immature Myeloid Cells in a Mouse Model

Abstract

Progesterone has been shown to regulate immunity during pregnancy, and progesterone administration may reduce inflammation-induced preterm labor. We sought to determine the maternal brain immune response to LPS-induced inflammation in pregnant and non-pregnant mice and whether additional progesterone supplementation attenuates this response. Pregnant (P: n = 9) and non-pregnant mice (NP: n = 9) were randomized to pretreatment with vaginal progesterone/carrier (Replens), daily from days 13 to 16. On days 15 and 16, LPS/saline was administered by intraperitoneal injection (Replens + saline n = 3; Replens + LPS n = 3; progesterone + LPS n = 3). Mice were sacrificed on day 16 and maternal serum analyzed for IL-6 levels and brains analyzed for nNOS, NF-kB, IL-6 protein levels and for immature myeloid cells (IMCs) and microglial activity. LPS significantly increased brain nNOS, NF-kB, and IL-6 in both NP and P mice, with significantly greater responses in P mice. In both NP and P groups, progesterone significantly attenuated LPS-induced increase of nNOS and NF-kB, however with no effect on serum IL-6. In the NP brains, LPS significantly increased IMC population and progesterone reduced the IMC phenotype to levels similar to controls. In P mice, neither LPS nor LPS + progesterone altered the brain IMC population. LPS significantly increased the microglial activity in both NP and P groups, which was attenuated by progesterone. Progesterone attenuates brain inflammatory response to LPS in both NP and P mice although it has no effect on systemic inflammation. In NP mice, progesterone attenuated the increase in brain IMC following LPS administration. Our results suggest that endogenous progesterone during pregnancy may protect the brain from LPS-induced inflammation.

Keywords: brain immune system; immature myeloid cells; inflammation; microglia; progesterone.

Fig. 1

Non-pregnant and pregnant mouse brain inflammatory pathways and brain and blood cytokine at basal state, following inflammation with or without progesterone pretreatment. Brain mean protein levels (u) of a nNOS, b NF-kB, c IL-6. d blood IL-6 protein levels. *p < 0.05, compared to the non-pregnant LPS group; **p < 0.05, compared to the pregnant LPS group.

Fig. 2

Non-pregnant and pregnant mouse brain IMCs and microglial activity at basal state, following inflammation with or without progesterone pretreatment. a microglia was gated as CD45^low; brain hematopoietic cells were gated as CD45^high. b–d CD45^highCD11b⁺Gr1⁺ IMCs in non-pregnant mice: Control, LPS, LPS + P respectively. e–g CD45^highCD11b⁺Gr1⁺ IMCs in pregnant mice: Control, LPS, LPS + P respectively. h the percentage of CD11b⁺Gr1⁺ IMCs out of CD45^high hematopoietic cells are plotted as mean ± SD. i microglial activity measured as medial CD45 intensity in CD45^low cells plotted as mean ± SD. *p < 0.05, compared to the non-pregnant LPS group; **p < 0.05, compared to the pregnant LPS group.