Abstract
BackgroundEstrogen signaling is indispensable for muscle regeneration, yet the role of estrogen in the development of muscle inflammation, especially in the intramuscular T cell response, and the influence on the intrinsic immuno-behaviors of myofibers remain largely unknown. We investigated this issue using the mice model of cardiotoxin (CTX)-induced myoinjury, with or without estrogen level adjustment.MethodsCTX injection i.m. (tibialis anterior, TA) was performed for preparing mice myoinjury model. Injection s.c. of 17β-estradiol (E2) or estrogen receptor antagonist 4-OHT, or ovariectomy (OVX), was used to change estrogen level of animal models in vivo. Serum E2 level was evaluated by ELISA. Gene levels of estrogen receptor (ERs) and cytokines/chemokines in inflamed muscle were monitored by qPCR. Inflammatory infiltration was observed by immunofluorescence. Macrophage and T cell phenotypes were analyzed by FACS. Immunoblotting was used to assess protein levels of ERs and immunomolecules in C2C12 myotubes treated with E2 or 4-OHT, in the presence of IFN-γ.ResultsWe monitored the increased serum E2 level and the upregulated ERβ in regenerated myofibres after myotrauma. The absence of estrogen in vivo resulted in the more severe muscle inflammatory infiltration, involving the recruitment of monocyte/macrophage and CD4+ T cells, and the heightened proinflammatory (M1) macrophage. Moreover, estrogen signaling loss led to Treg cells infiltration decrease, Th1 response elevation in inflamed muscle, and the markedly expression upregulation of immunomolecules in IFN-γ-stimulated C2C12 myotubes in vitro.ConclusionOur data suggest that estrogen is a positive intervention factor for muscle inflammatory response, through its effects on controlling intramuscular infiltration and phenotypes of monocytes/macrophages, on affecting accumulation and function of Treg cells, and on suppressing Th1 response in inflamed muscle. Our findings also imply an inhibition effect of estrogen on the intrinsic immune behaviors of muscle cells.
Highlights
Estrogen signaling is indispensable for muscle regeneration, yet the role of estrogen in the development of muscle inflammation, especially in the intramuscular T cell response, and the influence on the intrinsic immuno-behaviors of myofibers remain largely unknown
Acute myoinjury induces the enhancement of serum estrogen level and estrogen receptor Erβ expression in damaged muscle and in regenerated myofibres Using H&E and Dystrophin fluorescence staining, we observed that CTX injection in tibialis anterior (TA) muscle of B6 mice induced myofiber necrosis and degeneration at 3 days post-injury
It has been shown that the serum estradiol (E2) level elevated in the early stage of the trauma for the adult male and female patients, which suggests that estrogen may play an important role in protecting vital organs of traumatic patients [17,18,19]
Summary
Estrogen signaling is indispensable for muscle regeneration, yet the role of estrogen in the development of muscle inflammation, especially in the intramuscular T cell response, and the influence on the intrinsic immuno-behaviors of myofibers remain largely unknown. Estrogen exerts repressive effects on the innate immune, by increasing regulatory T cells (Tregs) frequency and number [9], controlling the expression of certain chemokine receptors in T cells [10], repressing monocytes and neutrophils to secrete proinflammatory cytokines in response to activating stimuli [11,12,13], or impairing natural killer (NK) cell cytotoxicity [14] Taken together, these findings suggest that estrogen signaling is important in establishing the balance of immunity and tolerance. Estrogen was reported to (i) reduce the number of wound neutrophils and diminish neutrophil localization at sites of inflammation [21], and (ii) augment estrogen receptor activity in immune cells and dampen innate immune signaling pathways in peripheral dendritic cells and macrophages [22,23,24] Anyway, it is still incompletely delineated how the estrogen milieu effects on the immune response trajectory of the damaged peripheral tissue soon after injury
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