Journal Article

Hypothalamo-pituitary and immune-dependent adrenal regulation during systemic inflammation

Tran, Nguyen, Alexaki, Vasileia-Ismini, Kanczkowski, Waldemar, Großklaus, Sylvia, Block, Norman L., Chavakis, Triantafyllos, Serially, Andrew V., Zacharowski, Kai, Popovics, Petra, Martinez, Antoine, Bornstein, Stefan R.

2013

Overview

Inflammation-related dysregulation of the hypothalamic–pituitary–adrenal (HPA) axis is central to the course of systemic inflammatory response syndrome or sepsis. The underlying mechanisms, however, are not well understood. Initial activation of adrenocortical hormone production during early sepsis depends on the stimulation of hypothalamus and pituitary mediated by cytokines; in late sepsis, there is a shift from neuroendocrine to local immune–adrenal regulation of glucocorticoid production. Therefore, the modulation of the local immune–adrenal cross talk, and not of the neuroendocrine circuits involved in adrenocorticotropic hormone production, may be more promising in the prevention of the adrenal insufficiency associated with prolonged sepsis. In the present work, we investigated the function of the crucial Toll-like receptor (TLR) adaptor protein myeloid differentiation factor 88 (MyD88) in systemic and local activation of adrenal gland inflammation and glucocorticoid production mediated by lipopolysachharides (LPSs). To this end, we used mice with a conditional MyD88 allele. These mice either were interbred with Mx1 Cre mice, resulting in systemic MyD88 deletion, predominantly in the liver and hematopoietic system, or were crossed with Akr1b7 Cre transgenic mice, resulting thereby in deletion of MyD88, which was adrenocortical-specific. Although reduced adrenal inflammation and HPA-axis activation mediated by LPS were found in Mx1 Cʳᵉ⁺-MyD88 ᶠˡ/ᶠˡ mice, adrenocortical-specific MyD88 deletion did not alter the adrenal inflammation or HPA-axis activity under systemic inflammatory response syndrome conditions. Thus, our data suggest an important role of immune cell rather than adrenocortical MyD88 for adrenal inflammation and HPA-axis activation mediated by LPS.

• Publisher: National Academy of Sciences
• Subject: Adrenal Cortex / Adrenal Cortex - cytology / Adrenal Cortex - drug effects / Adrenal Cortex - metabolism / Adrenal glands / Aldehyde Reductase / Aldehyde Reductase - genetics / Aldehyde Reductase - metabolism / alleles / Animal genetics / Animals / Biochemistry, Molecular Biology / Biological Sciences / Blotting, Western / Cancer / Carrier Proteins / Carrier Proteins - genetics / Carrier Proteins - metabolism / Cellular immunity / Chemokine CXCL2 / Chemokine CXCL2 - genetics / Chemokine CXCL2 - metabolism / corticotropin / Cytokines / Development Biology / Embryology and Organogenesis / Endocrinology and metabolism / Endothelial cells / Endotoxins / Female / Gene Expression / Genetics / Genomics / Glucocorticoids / Glucocorticoids - metabolism / Human health and pathology / Hypothalamo-Hypophyseal System / Hypothalamo-Hypophyseal System - drug effects / Hypothalamo-Hypophyseal System - physiology / hypothalamus / Inflammation / Inflammation - genetics / Inflammation - metabolism / Inflammation - physiopathology / Inflammatory diseases / Life Sciences / Lipopolysaccharides / Lipopolysaccharides - pharmacology / Liver / Male / Mice / Mice, Knockout / Mice, Transgenic / Molecular biology / Myeloid Differentiation Factor 88 / Myeloid Differentiation Factor 88 - genetics / Myeloid Differentiation Factor 88 - physiology / Myxovirus Resistance Proteins / Myxovirus Resistance Proteins - genetics / Myxovirus Resistance Proteins - metabolism / Neurochemistry / Physiology / Pituitary gland / Pituitary-Adrenal System / Pituitary-Adrenal System - drug effects / Pituitary-Adrenal System - immunology / Pituitary-Adrenal System - physiology / Reverse Transcriptase Polymerase Chain Reaction / Rodents / Sepsis / sepsis (infection) / Signal Transduction / Signal Transduction - drug effects / Toll like receptors / Toll-Like Receptors - metabolism / transgenic animals