The endocrine system participates in regulating macrophage maturation, although little is known about the modulating role of the thyroid hormones. In vitro results demonstrate a negative role of one such hormone, triiodothyronine (T3), in triggering the differentiation of bone marrow-derived monocytes into unpolarized macrophages. T3-induced macrophages displayed a classically activated (M1) signature. A T3-induced M1-priming effect was also observed on polarized macrophages because T3 reverses alternatively activated (M2) activation, whereas it enhances that of M1 cells. In vivo, circulating T3 increased the content of the resident macrophages in the peritoneal cavity, whereas it reduced the content of the recruited monocyte-derived cells. Of interest, T3 significantly protected mice against endotoxemia induced by lipopolysaccharide i.p. injection; in these damaged animals, decreased T3 levels increased the recruited (potentially damaging) cells, whereas restoring T3 levels decreased recruited and increased resident (potentially beneficial) cells. These data suggest that the anti-inflammatory effect of T3 is coupled to the modulation of peritoneal macrophage content, in a context not fully explained by the M1/M2 framework. Thyroid hormone receptor expression analysis and the use of different thyroid hormone receptor antagonists suggest thyroid hormone receptor β1 as the major player mediating T3 effects on macrophages. The novel homeostatic link between thyroid hormones and the pathophysiological role of macrophages opens new perspectives on the interactions between the endocrine and immune systems.

Macrophages can be divided on basis of their function: classically activated macrophages (often referred to as M1) and alternatively activated macrophages (typically named M2). There is evidence that different endocrine stimuli influence macrophages differentiation with a mosaic of different and overlapping characteristics. In this study, we verified for the first time the role of thyroid hormone (TH) system on macrophage differentiation/polarization through in vitro and in vivo approaches. Monocites were isolated from femur bone marrow derived cells and primary cultures of differentiated macrophages (MΦ) were obtained. MΦ were also polarized to generate M1 and M2 subtypes. In these cells, we demonstrated different levels of TH receptors (TRalfa1, TRbeta1, and TRbeta2). Cells were then treated with TH during MΦ differentiation, as well as during polarization to M1 or M2, and the hormone‐induced effects were determined. For instance, a set of specific cell‐surface molecules and cytokine/receptor genes were measured. In addition, we determined TH effects on cell proliferation, cell viability, phagocytosis, nitric oxide synthase and arginase protein expression, cytokine release, and cell migration. In vivo experiments were also conducted in euthyroid and hypothyroid mice. In particular, we analysed the animal survival rate and the presence of cell‐surface molecules in peritoneal macrophages of mice both in control conditions and during systemic inflammation. Taken toghether, our data suggest that TH has a role in modulating specific properties of macrophage populations and the functional balance M1/M2.