Regulatory T Cells Promote Myositis and Muscle Damage in Toxoplasma gondii Infection

Abstract

The coordination of macrophage polarization is essential for the robust regenerative potential of skeletal muscle. Repair begins with an inflammatory monocyte/pro-inflammatory macrophage (M1)-mediated phase followed by polarization to a pro-regenerative (M2) phenotype. Recently, regulatory T cells (Tregs) were described as necessary for this M1 to M2 transition. Here, we report that chronic infection with the protozoan parasite Toxoplasma gondii causes a non-resolving Th1 myositis with prolonged tissue damage associated with persistent M1 accumulation. Surprisingly, Treg ablation during chronic infection rescues macrophage homeostasis and skeletal muscle fiber regeneration showing that Tregs can directly contribute to muscle damage. This study provides evidence that the tissue environment established by the parasite could lead to a paradoxical pathogenic role for Tregs. As such, these findings should be considered when tailoring therapies directed at Tregs in inflammatory settings.

‘Repair’ Treg Cells in Tissue Injury

“…However, paradoxical pathogenic roles for Tregs were reported in chronic muscle injury infected with Toxoplasma gondii . Jin et al showed that prolonged tissue damage was associated with persistent pro-inflammatory macrophage accumulation, whereas Treg ablation during this process rescued macrophage homeostasis and skeletal muscle fibre regeneration [26]. Thus, the key to interpreting the role of Tregs in muscle damage is the tissue environment established by the injury signal.…”

Therapeutic Administration of IL-10 and Amphiregulin Alleviates Chronic Skeletal Muscle Inflammation and Damage Induced by Infection

“…Chronic infections of the skeletal muscle have previously been shown to severely alter the tissue immune landscape and compromise immune-regulatory networks (7, 18–20). Toxoplasma gondii is an obligate intracellular parasite capable of establishing a chronic infection in the CNS and striated muscle tissues (21).…”

“…A robust interferon-gamma (IFNγ)-mediated immune response is necessary to control infection (21). Recently, we showed chronic skeletal muscle infection with Toxoplasma gondii drastically alters skeletal muscle immunity and leads to long-term muscle damage and myositis (18). Tregs decrease in frequency and also highly express the Th1-lineage specific transcription factor Tbet in infected skeletal muscle (18).…”

“…Recently, we showed chronic skeletal muscle infection with Toxoplasma gondii drastically alters skeletal muscle immunity and leads to long-term muscle damage and myositis (18). Tregs decrease in frequency and also highly express the Th1-lineage specific transcription factor Tbet in infected skeletal muscle (18). Furthermore, in this setting, Tregs pathogenically promote long-term muscle damage and accumulation of inflammatory macrophages in the skeletal muscle (18).…”

“…Tregs decrease in frequency and also highly express the Th1-lineage specific transcription factor Tbet in infected skeletal muscle (18). Furthermore, in this setting, Tregs pathogenically promote long-term muscle damage and accumulation of inflammatory macrophages in the skeletal muscle (18). …”