Toll-like receptor 2 (TLR2) engages endoplasmic reticulum stress sensor IRE1α to regulate retinal innate responses in Staphylococcus aureus endophthalmitis.

Abstract

Endoplasmic reticulum (ER) stress response has been implicated in a variety of pathophysiological conditions, including infectious and inflammatory diseases. However, its contribution in ocular bacterial infections, such as endophthalmitis, which often cause blindness is not known. Here, using a mouse model of Staphylococcus (S.) aureus endophthalmitis, our study demonstrates the induction of inositol-requiring enzyme 1α (IRE1α) and splicing of X-box binding protein-1 (Xbp1) branch of the ER-stress pathway, but not the other classical ER stress sensors. Interestingly, S aureus-induced ER stress response was found to be dependent on Toll-like receptor 2 (TLR2), as evident by reduced expression of IRE1α and Xbp1 mRNA splicing in TLR2 knockout mouse retina. Pharmacological inhibition of IRE1α using 4µ8C or experiments utilizing IRE1α-/- macrophages revealed that IRE1α positively regulates S aureus-induced inflammatory responses. Moreover, IRE1α inhibition attenuated S aureus-triggered NF-κB, p38, and ERK pathways activation and cells treated with these pathway-specific inhibitors reduced Xbp1 splicing, suggesting a positive feedback inhibition. In vivo, inhibition of IRE1α diminished the intraocular inflammation and reduced PMN infiltration in mouse eyes, but, increased the bacterial burden and caused more retinal tissue damage. These results revealed a critical role of the IRE1α/XBP1 pathway as a regulator of TLR2-mediated protective innate immune responses in S aureus-induced endophthalmitis.

• Authors: Ajay Kumar, Pawan Kumar Singh, Kezhong Zhang, Ashok Kumar
• Journal: FASEB journal : official publication of the Federation of American Societies for Experimental Biology (FASEB J) Vol. 34 Issue 10 Pg. 13826-13838 (10 2020) ISSN: 1530-6860 [Electronic] United States
• PMID: 32813318 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: © 2020 Federation of American Societies for Experimental Biology.

Chemical References

• NF-kappa B
• Tlr2 protein, mouse
• Toll-Like Receptor 2
• X-Box Binding Protein 1
• Xbp1 protein, mouse
• Ern1 protein, mouse
• Protein Serine-Threonine Kinases
• p38 Mitogen-Activated Protein Kinases
• Endoribonucleases

Topics

• Animals
• Cell Line
• Cells, Cultured
• Endophthalmitis (genetics, immunology)
• Endoribonucleases (genetics, metabolism)
• Female
• Immunity, Innate
• MAP Kinase Signaling System
• Male
• Mice
• Mice, Inbred C57BL
• NF-kappa B (metabolism)
• Protein Serine-Threonine Kinases (genetics, metabolism)
• Retina (immunology, microbiology)
• Staphylococcus aureus (pathogenicity)
• Toll-Like Receptor 2 (genetics, metabolism)
• X-Box Binding Protein 1 (genetics, metabolism)
• p38 Mitogen-Activated Protein Kinases