Changes in Thyroid Hormone Receptors After Permanent Cerebral Ischemia in Male Rats

Abstract

Thyroid hormones (TH) and receptors (TRs) may play an important role in the pathophysiology of acute cerebral ischemia. In the present study, we sought to determine whether serum triodothyronine (T3)/thyroxine (T4) and brain TRs (TRα1, TRβ1) might change after experimental stroke. Male adult Wistar rats were subjected to permanent middle cerebral artery occlusion (group P) and compared to sham-operated controls (group S). Animals were followed clinically for 14 days until brain collection for Western blot (WB) or neuropathological analysis of TRs in three different brain areas (infarcted tissue, E1; noninfarcted ipsilateral hemisphere, E2; and contralateral hemisphere, E3). Analysis of serum TH levels showed a reduction of T4 in group P (p = 0.002) at days 2 to 14, while half of the animals also displayed "low T3" values (p = 0.012) on day 14. This T4 reduction was inversely correlated to the clinical severity of stroke and the concomitant body weight loss (p < 0.005). WB analysis of TRα1 and TRβ1 protein expression showed heterogenic responses at day 14: total and nuclear TRα1 were similar between the two groups, while total TRβ1 decreased 7.5-fold within E1 (p ≤ 0.001) with a concomitant 1.8-fold increase of nuclear TRβ1 in E2 area (p = 0.03); TRβ1 expression did not differ in E3. Neuropathological analysis revealed that activated macrophages/microglia exclusively expressed nuclear TRα1 within the infarct core. Astrocytes mildly expressed nuclear TRα1 in and around the infarct, along with a prominent TRβ nuclear signal restricted in the astrocytic scar. Neurons around the infarct expressed mainly TRα1 and, to a milder degree, TRβ. Surprisingly enough, we detected for the first time a TRβ expression in the paranodal region of Ranvier nodes, of unknown significance so far. Our data support that cerebral ischemia induces a low TH response, associated with significant and heterogenic changes in brain TR expression. These findings could imply an important role of TH signaling in cerebral ischemia.

Thyroid Hormone Action on Innate Immunity

“…Modifications in the homeostatic conditions of the nervous tissue promote microglia activation, release of inflammatory mediators and phagocytosis of degenerating cells (74). Lima et al (75) reported that rat microglial cells in culture express TRα and TRβ, whereas other authors did not observe the latter (76). αVβ3 integrin has also been described in these cells (77), and in mice microglia, the TH transporters OATP4A1, LAT2, and MCT10 were also found (78, 79).…”

Associations between Thyroid Stimulating Hormone Levels and Both Severity and Early Outcome of Patients with Ischemic Stroke

“…Third, TSH blood samples were collected at different times from stroke onset, and there exists the possibility to question the influence of brain infarction on thyroid function. In rats subjected to permanent middle cerebral artery occlusion, brain ischemia was associated with a decrease in thyroxin (T4) hormone levels after 2 days [20] . In addition, in a study conducted on patients with large hemispheric IS, it was shown that changes in TSH, triiodothyronine (T3) and thyroxin (T4) hormone levels were observed after 3 days [21] .…”

Thyroid hormone metabolism in innate immune cells

“…Microglia, the resident macrophages of the brain, contain the TH transporters LAT2, MCT10 and OATP4a1 (Wirth et al 2009, Braun et al 2011. Macrophages were also found to express D2 (Kwakkel et al 2014), TRα1 and possibly also TRβ although authors have reported conflicting results (Billon et al 2014, Kwakkel et al 2014, Lourbopoulos et al 2014, Perrotta et al 2014. Several recent papers have demonstrated that both human and murine macrophages are able to produce a functional TSHβ splice variant that is positively regulated by T 3 and capable of stimulating the TSH receptor (Vincent et al 2009, Baliram et al 2013, 2016.…”