Long term alterations in neuroimmune responses of female rats after neonatal exposure to lipopolysaccharide
Introduction
Exposure to an infection or an immune stimulant such as lipopolysaccharide (LPS) induces synthesis of pro-inflammatory cytokines, for example interleukin (IL)-1β and IL-6, causing an acute-phase response of which one component is fever. This febrile response is an integral part of the host defense against the invasion of pathogens, and is associated with an increased ability to combat infection and increased survival (Blatteis et al., 2000).
It is well established, however, that there are significant gender related differences, in humans and other mammals in the response to an immune challenge and that the sex hormones progesterone and estrogen are important in these differential responses (Martin, 2000). It is known that female rodents display greater hypothalamic–pituitary–adrenal (HPA) axis responses to immune challenge (Watanobe and Yoneda, 2003). Females have higher peak basal corticosterone levels as well as greater increases in corticosterone and adrenocorticotropic hormone (ACTH) in response to LPS compared with male rats (Critchlow et al., 1963, Seale et al., 2004, Watanobe and Yoneda, 2003). Female rats also display a significantly lower second phase febrile response to intraperitoneal (i.p.) LPS (Taylor et al., 2005), a reduction most likely due to estrogen and progesterone (Mouihate and Pittman, 2003).
It is particularly interesting that a variety of interventions and perturbations during the neonatal period, including maternal separation, neonatal handling, and immune challenge result in gender specific alterations in the adult (Barr et al., 2004, McCormick et al., 1995, Papaioannou et al., 2002, Park et al., 2003, Smythe et al., 1994, Weinberg et al., 1978). We have previously reported that male rats exposed as neonates at postnatal day (P)14 to LPS have elevated basal hypothalamic cyclooxygenase (COX)-2 levels, as well as attenuated febrile and COX-2 responses to a further dose of LPS in adulthood (Boissé et al., 2004, Ellis et al., 2005), while the response to LPS eight weeks after adult LPS pre-treatment is not affected (Boissé et al., 2004). Thus, neonatal exposure to an immune challenge, in the form of LPS, can alter centrally mediated inflammatory responses in adult male rats.
Given the differences in the innate immune responses of males and females, we therefore wanted to determine whether neonatal exposure to LPS alters adult COX-2 and febrile responses in female rats in a similar manner to that previously observed in the males. Thus, P14 female rats were administered an i.p. injection of either pyrogen-free saline (controls), Escherichia coli LPS, or Salmonella enteritidis LPS. Once these rats reached adulthood they were assessed for temperature, activity and COX-2 responses to a further injection of LPS to test whether neonatal exposure to an immune challenge also alters febrile and neurochemical responses to LPS in adult females.
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Animals
Pregnant Sprague–Dawley rats (Charles River) were maintained at 22 °C on a 12 h light/dark cycle (8:00 am–8:00 pm) with pelleted rat chow and water available ad libitum. On the day of birth, i.e., P0, litters were culled to 12 pups and pups were randomly distributed among the dams. All litters were weaned at P21 and female rats were housed 3–4 animals per cage until they were between 8 and 12 weeks of age. All procedures were conducted in accordance with the Canadian Council on Animal Care
Neonatal exposure to LPS attenuates the febrile response to LPS in adulthood
Prior to adult LPS exposure, circadian temperature rhythms of the female rats treated as neonates with LPS were identical to those treated as neonates with saline (data not shown). Thus, baseline temperatures of neonatally LPS-treated (n = 12) and saline-treated (n = 10) were identical (Fig. 1A). All rats displayed the expected injection-associated fever of approximately 1 °C that peaked at approximately 45 min after the injection. In rats given saline as adults, temperatures returned to baseline
Discussion
The results of the present investigation show that neonatal exposure to LPS leads to an attenuation of the febrile response to an adult LPS challenge in female rats in an identical manner to that previously seen in males (Boissé et al., 2004). This altered response was seen in response to both homologous LPS (i.e., neonatal E. coli followed by adult E. coli) and to heterologous stimuli (i.e., neonatal S. enteriditis followed by adult E. coli). A reduction in the amount of inducible COX-2 after
Acknowledgments
This work was supported by the Canadian Institutes of Health Research (CIHR). L.B was an Alberta Heritage Foundation for Medical Research (AHFMR) student. S.J.S. is an AHFMR postdoctoral fellow. Q.J.P. is an AHFMR Medical Scientist.
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2020, Neurochemistry InternationalCitation Excerpt :On the other hand, even with all these observations, it would be interesting to examine sex differences in the future given what is known for females versus males in other models and even offer predictions for females in the present model. About the choice of time of preconditioning with LPS in neonatal period, authors have shown that a single intraperitoneal injection of LPS, at postnatal day 14, programme an attenuated febrile response to a further, immune challenge of the same type in rats (Ellis et al., 2006; Spencer et al., 2010, 2006b, 2006a). On the other hand, was found in male rats that when the initial exposure to LPS is given during adulthood, there is no such attenuated febrile response to further LPS exposure eight weeks later and no change in adult LPS responses when male rats are given their first challenge at postnatal day 28 (Boissé et al., 2004).
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These authors contributed equally to this work.