Thyroid Hormone Enhances Nitric Oxide-Mediated Bacterial Clearance and Promotes Survival after Meningococcal Infection

Abstract

Euthyroid sick syndrome characterized by reduced levels of thyroid hormones (THs) is observed in patients with meningococcal shock. It has been found that the level of THs reflects disease severity and is predictive for mortality. The present study was conducted to investigate the impact of THs on host defense during meningococcal infection. We found that supplementation of thyroxine to mice infected with Neisseria meningitidis enhanced bacterial clearance, attenuated the inflammatory responses and promoted survival. In vitro studies with macrophages revealed that THs enhanced bacteria-cell interaction and intracellular killing of meningococci by stimulating inducible nitric oxide synthase (iNos)-mediated NO production. TH treatment did not activate expression of TH receptors in macrophages. Instead, the observed TH-directed actions were mediated through nongenomic pathways involving the protein kinases PI3K and ERK1/2 and initiated at the membrane receptor integrin αvβ3. Inhibition of nongenomic TH signaling prevented iNos induction, NO production and subsequent intracellular bacterial killing by macrophages. These data demonstrate a beneficial role of THs in macrophage-mediated N. meningitidis clearance. TH replacement might be a novel option to control meningococcal septicemia.

Thyroid hormone metabolism in innate immune cells

“…This is illustrated by the fact that ROS production and MPO activity are increased in hyperthyroid neutrophils (Videla et al 1993, Fernandez & Videla 1995, Szabo et al 1996, Magsino et al 2000, Mezosi et al 2005, Russo-Carbolante et al 2005b, Marino et al 2006. Higher TH levels also increase reactive nitrogen species production, phagocytosis and bacterial killing in macrophages , Chen et al 2012. In accordance with these effects, T 3 has been shown to polarize macrophages towards a pro-inflammatory M1 phenotype, whilst inhibiting anti-inflammatory M2 markers (Perrotta et al 2014).…”

“…In macrophages, another non-genomic pathway has been described involving binding of extracellular TH to integrin αvβ3, resulting in activation of the ERK and PI3K signalling pathways (Fig. 2) (Chen et al 2012). The effects of T 3 stimulation in dendritic cells are mediated via TRβ 1 and the Akt and NFκB pathways (Fig.…”

“…It should be noted that the majority of these studies assessed a mixed population of mononuclear cells containing significant numbers of other cell types, making it impossible to determine the contribution of the macrophage/monocyte subset. Recently, TH administration was found to increase iNOS expression, nitrite production and in vitro bacterial killing in both a human and a mouse macrophage cell line and treatment with TH increased the survival after meningococcal infection in mice (Chen et al 2012).…”

“…(A) The effects of TH in macrophages are mediated through integrin αvβ3 or through modulation of intracellular TH levels. TH can bind to integrin αvβ3 on the macrophage cell surface resulting in the activation of PI3K and ERK1/2 pathways followed by the upregulation of inducible nitric oxide synthase (iNOS) (Chen et al 2012). Alternatively, TH can enter the cell through TH transporters MCT8 or MCT10 after which the prohormone T 4 is converted to active hormone T 3 by type 2 deiodinase (D2) resulting in increased phagocytosis and cytokine response.…”

“…The TH-induced increase in iNOS expression and activity, phagocytosis and bacterial killing is thought to be partly mediated via binding of TH to integrin αvβ3 on the extracellular surface of the cell, which results in the rapid activation of the PI3K and ERK1/2 signalling pathways ( Fig. 2A) (Chen et al 2012).…”