Tryptophanyl tRNA synthetase (WRS) is an essential enzyme as it catalyzes the ligation of tryptophan to its cognate tRNA during translation. Interestingly, mammalian WRS has evolved to acquire domains or motifs for novel functions beyond protein synthesis; WRS can also further expand its functions via alternative splicing and proteolytic cleavage. WRS is localized not only to the nucleus but also to the extracellular space, playing a key role in innate immunity, angiogenesis, and IFN-γ signaling. In addition, the expression of WRS varies significantly in different tissues and pathological states, implying that it plays unique roles in physiological homeostasis and immune defense. This review addresses the current knowledge regarding the evolution, structural features, and context-dependent functions of WRS, particularly focusing on its roles in immune regulation.

Tumor necrosis factor-alpha (TNF-α) is a well-known pro-inflammatory cytokine responsible for the modulation of the immune system. TNF-α plays a critical role in almost every type of inflammatory disorder, including central nervous system (CNS) diseases. Although TNF-α is a well-studied component of inflammatory responses, its functioning in diverse cell types is still unclear. TNF-α functions through its two main receptors: tumor necrosis factor receptor 1 and 2 (TNFR1, TNFR2), also known as p55 and p75, respectively. Normally, the functions of soluble TNF-α-induced TNFR1 activation are reported to be pro-inflammatory and apoptotic. While TNF-α mediated TNFR2 activation has a dual role. Several synthetic drugs used as inhibitors of TNF-α for diverse inflammatory diseases possess serious adverse effects, which make patients and researchers turn their focus toward natural medicines, phytochemicals in particular. Phytochemicals targeting TNF-α can significantly improve disease conditions involving TNF-α with fewer side effects. Here, we reviewed known TNF-α inhibitors, as well as lately studied phytochemicals, with a role in inhibiting TNF-α itself, and TNF-α-mediated signaling in inflammatory diseases focusing mainly on CNS disorders.

Tryptophanyl-tRNA synthetase 1 (WARS1) is an endogenous ligand of mammalian Toll-like receptors (TLR) 2 and TLR4. Microarray data, using mRNA from WARS1-treated human peripheral blood mononuclear cells (PBMCs), had indicated WARS1 to mainly activate innate inflammatory responses. However, exact molecular mechanism remains to be understood. The triggering receptor expressed on myeloid cells (TREM)-1 is an amplifier of pro-inflammatory processes. We found WARS1 to significantly activate TREM-1 at both mRNA and protein levels, along with its cell surface expression and secretion in macrophages. WARS1 stimulated TREM-1 production via TLR2 and TLR4, mediated by both MyD88 and TRIF, since targeted deletion of TLR4, TLR2, MyD88, and TRIF mostly abrogated TREM-1 activation. Furthermore, WARS1 promoted TREM-1 downstream phosphorylation of DAP12, Syk, and AKT. Knockdown of TREM-1 and inhibition of Syk kinase significantly suppressed the activation of inflammatory signaling loop from MyD88 and TRIF, leading to p38 MAPK, ERK, and NF-κB inactivation. Finally, MyD88, TRIF, and TREM-1 signaling pathways were shown to be cooperatively involved in WARS1-triggered massive production of IL-6, TNF-α, IFN-β, MIP-1α, MCP-1, and CXCL2, where activation of Syk kinase was crucial. Taken together, our data provided a new insight into WARS1′s strategy to amplify innate inflammatory responses via TREM-1.

Secondary hemophagocytic lymphohistiocytosis/macrophage activation syndrome (sHLH/MAS) is a life-threatening immune disorder triggered by rheumatic disease, infections, malignancies, or medications. Characterized by the presence of hemophagocytic macrophages and a fulminant cytokine storm, sHLH/MAS leads to hyperferritinemia and multiorgan failure and rapidly progresses to death. The high mortality rate and the lack of specific treatments necessitate the development of a new drug. However, the complex and largely unknown immunopathologic mechanisms of sHLH/MAS, which involve dysfunction of various immune cells, diverse etiologies, and different clinical contexts make this effort challenging. This review introduces the terminology, diagnosis, and clinical features of sHLH/MAS. From a translational perspective, this review focuses on the immunopathological mechanisms linked to various etiologies, emphasizing potential drug targets, including key molecules and signaling pathways. We also discuss immunomodulatory biologics, existing drugs under clinical evaluation, and novel therapies in clinical trials. This systematic review aims to provide insights and highlight opportunities for the development of novel sHLH/MAS therapeutics.

Soojung Yoon, Hamid Iqbal, Sun Mi Kim and Mirim Jin. Biomolecules & Therapeutics -0001;0:. https://doi.org/10.4062/biomolther.2022.116

Jin M, et al. Immune Netw. 2018 Nov;18(6):e42. https://doi.org/10.4110/in.2018.18.e42