Lysyl–Transfer RNA Synthetase Induces the Maturation of Dendritic Cells through MAPK and NF-κB Pathways, Strongly Contributing to Enhanced Th1 Cell Responses

Abstract

In addition to essential roles in protein synthesis, lysyl-tRNA synthetase (KRS) is secreted to trigger a proinflammatory function that induces macrophage activation and TNF-a secretion. KRS has been associated with autoimmune diseases such as polymyositis and dermatomyositis. In this study, we investigated the immunomodulatory effects of KRS on bone marrow-derived dendritic cells (DCs) of C57BL/6 mice and subsequent polarization of Th cells and analyzed the underlying mechanisms. KRS-treated DCs increased the expression of cell surface molecules and proinflammatory cytokines associated with DC maturation and activation. Especially, KRS treatment significantly increased production of IL-12, a Th1-polarizing cytokine, in DCs. KRS triggered the nuclear translocation of the NF-kB p65 subunit along with the degradation of IkB proteins and the phosphorylation of MAPKs in DCs. Additionally, JNK, p38, and ERK inhibitors markedly recovered the degradation of IkB proteins, suggesting the involvement of MAPKs as the upstream regulators of NF-kB in the KRS-induced DC maturation and activation. Importantly, KRS-treated DCs strongly increased the differentiation of Th1 cells when cocultured with CD4 + T cells. The addition of anti-IL-12-neutralizing Ab abolished the secretion of IFN-g in the coculture, indicating that KRS induces Th1 cell response via DC-derived IL-12. Moreover, KRS enhanced the OVA-specific Th1 cell polarization in vivo following the adoptive transfer of OVA-pulsed DCs. Taken together, these results indicated that KRS effectively induced the maturation and activation of DCs through MAPKs/NF-kB-signaling pathways and favored DC-mediated Th1 cell response.

MHC class I and II peptide homology regulates the cellular immune response

“…Recent elegant work demonstrated that multiple mARS subunit components are differentially phosphorylated and dissociate from the complex in response to vesicular stomatitis virus (VSV) and influenzavirus infection. Once dissociated, these subunits bind and activate essential components of innate antiviral immunity, thereby implicating the mARS as both a sensor and regulator of the immune response to viral infection 68,69 . Canonically, the mARS complex is reported to possess only 8 of the 19 known mammalian aminoacyl‐tRNA synthetase isoforms (glutamyl‐prolyl, isoleucyl, leucyl, glutaminyl, methionyl, lysyl, arginyl, and aspartyl) 40,64,65,68 which, if true under all homeostatic conditions, could limit its utility as a sensor capable of discerning amino acid homology between epitopes not possessing one or more of the cognate amino acid residues.…”

The tRNA‐associated dysregulation in immune responses and immune diseases

“…101 Meanwhile, adoptive transfer of KRS-treated DCs could effectively induce the polarization of Th1 cells and inhibit tumour growth in mice, indicating that KRS enhanced DC-mediated Th1 cell responses. Lysyl-tRNA synthetase (KRS) induced the maturation of DCs and promoted the production of IL-12 in DCs by regulating the MAPK and NF-κB pathways.…”

“…Lysyl-tRNA synthetase (KRS) induced the maturation of DCs and promoted the production of IL-12 in DCs by regulating the MAPK and NF-κB pathways. 101 Meanwhile, adoptive transfer of KRS-treated DCs could effectively induce the polarization of Th1 cells and inhibit tumour growth in mice, indicating that KRS enhanced DC-mediated Th1 cell responses. Hildebrand et al found that an Hsa-miR-99b/let-7e/miR-125a cluster could stabilize signal transducer and activator of transcription 3 (STAT3) activity and thus modulate the suppressive antigen-presenting cells (APCs) stimulated by pathogen recognition receptor.…”

“…A, KRS induced DC maturation and promoted IL-12 production by regulating MAPK and NF-κB pathways, contributing to enhanced Th1 cell responses. 101 B, Apoptotic cells secreted TyrRS, which was cleaved into MiniTyr and EMAP fragments by Mmp. EMAP recruited macrophages to the dead cells by activating PI3K, thereby removing dying loser cells.…”

GVS-12 attenuates non-alcoholic steatohepatitis by suppressing inflammatory responses via PPARγ/STAT3 signaling pathways

“…For example, the activation of p38 mitogen-activated protein kinase (MAPKs) signal pathways, nuclear factor kappa-light-chainenhancer of activated B cells (NF-kB) signal pathways and signal transducer and activator of transcription 3 (STAT3) signal pathways could promote the production of the proinammatory cytokines. 5 In contrast, the inhibitors of these signal pathways could reduce the production of proinammatory cytokines aforementioned. Accumulative evidence suggested that STAT3 signal pathway played a vital role in the production of proin-ammatory cytokines in NASH.…”