Fig. 3: Roles of WRS in “Yin-Yang” immune regulation and its relation to immune diseases.

a Upon infection, FL-WRS is rapidly secreted from monocytes to activate macrophages via TLR4/MD2, which induces innate immune responses, including chemokine production, neutrophil infiltration, and increased phagocytosis, eventually leading to pathogen elimination. High levels of WRS probably provoke an acute hyper-inflammation in sepsis. Antigen presentation to T cells by dendritic cells induces IFN-γ production, leading to the increased expression of WRS. Overexpression of WRS in T cells is able to reserve Trp, which is essential for cell activation and proliferation and may be involved in the development of autoreactive T cells in autoimmune diseases. b IFN-γ stimulation not only increases WRS secretion but also induces the translocation of WRS into the nucleus. Secreted WRS is proteolytically processed to form T2-WRS, which binds to VE-cadherin and inhibits angiogenesis. Nuclear FL-WRS enhances anti-angiogenesis by regulating cell growth through the phosphorylation of p53, further implying a role for WRS as an anti-cancer agent. Furthermore, an imbalanced activation of indoleamine 2,3-dioxygenase (IDO) relative to WRS in antigen-presenting cells (APCs), including macrophages and dendritic cells, induces an immunosuppressive state, inhibiting the proliferation of immune cells, including T cells, and possibly causing these cells to become tolerant or apoptotic