TLR activation of the transcription factor XBP1 regulates innate immune responses in macrophages

Fabio Martinon et al. Nature immunology 11: 411-418 (2010)

Student:  Huo-Sheng Chiou (邱穫升)                            Time: 14:00~15:00, Nov. 10, 2010

Commentator: Dr. Li-Jin Hsu (徐麗君 老師)              Place: Room 601

Abstract

Toll-like receptors (TLR) are essential sensors of immune system for recognizing a broad spectrum of microbial structures. Activation of TLRs promotes innate and adaptive responses through recruiting different adapters involved in multitude signaling platforms. Formation of TLR-proximal signaling complexes will finally trigger the sequential cascade of transcriptional regulatory events that modulate expression of individual genes (such as those encoding proinflammatory cytokines) transiently. This transcriptional regulation accurately controls activated immune program (1). The endoplasmic reticulum (ER) is an organelle that contributes to orchestrat protein-folding in cells. ER stress is generated from an accumulation of unfolded or misfolded proteins. The accumulation triggers unfolded protein response and activation of two parallel kinases IRE1 and PERK, and a transcription factor precursor ATF6 for rescuing ER stress. The signal branch of IRE1 is formed by IRE-dependent cytosolic mRNA-splicing event that generates mature XBP1 protein. The mature XBP1 functions as a transcription factor of ER-stress-related gene and helps ER back to homeostasis (2). Previous large-scale gene-expression studies have shown the difference of XBP1 mRNA expression after TLR stimulation. Also, some ER-stress markers have been detected after TLR stimulation. Based on these results, the authors are intended to understand the correlation between ER signaling and innate immunity. The authors discovered that the maturation of XBP1 mRNA by TLR4 and TLR2-stimulated IRE1-XBP1 pathway required NADPH oxidase NOX2 together with TRAF6 in J774 cells and bone marrow-derived macrophages from transgenic mice. Using NADPH oxidase inhibitor and NOX2-deficient macrophages, the authors had shown that TLR activation of IRE1-XBP1 pathway was ROS-dependent. Unexpectedly, TLR-induced maturation of XBP1 in macrophages was ER-stress independent since there was no activation of ER-stress marker (such as PERK and ATF6). To investigate the role of XBP1 in TLR signaling, the author detected the expression of cytokines (IL-6, TNF, IL-8, etc.) in macrophage after ER stress and bacterial infection. The results identified the role of XBP1 in sustained production of TLR4 and TLR2-inducedproinflammatory cytokines (IL-6). Also, production of IL-6 was enhanced by ER stress though IRE1-XBP1 pathway. Taken together, this study indicates that XBP1 is a positive regulator of TLR gene induction and the ER stress promotes the inflammation of innate response. Also, the authors provide a novel IRE1-XBP1 signal pathway in TLR response which presents a new therapeutic strategy for harmful TLR-mediated inflammation.

References

1.      Alex E. et al. Unfolding new roles for XBP1 in immunity. Nature immunology 11: 365-366 (2010)

2. Kezhong Z. et al. From endoplasmic-reticulum stress to the inflammatory response. Nature 454: 455-462 (2008)