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Reply to Karadag: does steroid increase LPS-induced sickness behaviors?

Neuropsychopharmacology (2024)Cite this article

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Replying to Martz J et al. Neuropsychopharmacology https://doi.org/10.1038/s41386-024-01838-x (2024)

Karadag et al. [1] were concerned that the corticosterone inhibitor, metyrapone, reversed the effect of lipopolysaccharide (LPS) on sickness behavior. While not the focus of our paper, we also find it interesting that maternal sickness responses were decreased in rat dams that received metyrapone and LPS. Classically, corticosteroids are thought to be anti-inflammatory and can be used to treat endotoxemia, yet here its inhibition was associated with reductions in sickness behaviors and their associated plasma cytokines following LPS. As mentioned in our article, the differential LPS-induced cytokine profiles (inhibition/activation) across studies likely depend on the reproductive status of the animal, as well as on methodological aspects of the LPS dose and timing of plasma cytokine sampling. It is important to point out that the evidence supplied by Karadag et al., that corticosteroids decrease endotoxemia, came from human and rodent studies that did not account for pregnancy, which is the physiological state we studied here. Pregnancy is complicated in terms of immune and endocrine integration and known pharmacodynamic differences are poorly understood due to its low representation in research. Moreover, while women were included in some of the clinical data they highlighted, sex differences were not assessed. Even within females, different manifestations of plasma cytokine expression (including suppression) are reported in rats based on reproductive status in response to combined LPS and metyrapone treatment [2, 3]. Cytokines themselves have traditionally been categorized as either pro- or anti-inflammatory, which we now know is context specific. The same is true for glucocorticoids; for example, the low corticosterone levels that accompany TLR2 deficiency are associated with impaired inflammatory activation in the presence of LPS [4]. Metyrapone is not a specific 11β-hydroxylase inhibitor and can increase testosterone (immunosuppressant) in women [5]; therefore, a non-corticosterone mediated pathway may impart anti-inflammatory actions with this drug. However, the underlying mechanisms of this were beyond the scope of our paper. Additionally, the animal study cited in their comment [6] used high dose LPS in male rats to model severe sepsis and septic shock, which our low dose LPS animal model does not. Consequently, metyrapone is not protecting against the sickness severity associated with septic shock but instead a much milder reaction.

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Acknowledgements

This work is funded by NIMH under Award Numbers R15MH114035 (to ACK) and R01MH120066 (to MLS). The content is solely the responsibility of the authors and does not necessarily represent the official views of any of the financial supporters.

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  1. School of Arts & Sciences, Health Psychology Program, Massachusetts College of Pharmacy and Health Sciences, Boston, MA, 02115, USA

    Julia Martz, Laurel Geist & Amanda C. Kentner

  2. Department of Psychiatry, University of Pittsburgh, 450 Technology Drive, Pittsburgh, PA, 15219, USA

    Micah A. Shelton & Marianne L. Seney

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  1. Julia Martz
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JM, MAS, LG, MLS, & ACK wrote and edited this content together.

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Correspondence to Marianne L. Seney or Amanda C. Kentner.

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Martz, J., Shelton, M.A., Geist, L. et al. Reply to Karadag: does steroid increase LPS-induced sickness behaviors?. Neuropsychopharmacol. (2024). https://doi.org/10.1038/s41386-024-01839-w

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