Inflammatory ER stress responses dictate the immunopathogenic progression of systemic candidiasis
Deepika Awasthi, Sahil Chopra, Byuri A. Cho, Alexander Emmanuelli, Tito A. Sandoval, Sung-Min Hwang, Chang-Suk Chae, Camilla Salvagno, Chen Tan, Liliana Vasquez-Urbina, Jose J. Fernandez Rodriguez, Sara F. Santagostino, Takao Iwawaki, E. Alfonso Romero-Sandoval, Mariano Sanchez Crespo, Diana K. Morales, Iliyan D. Iliev, Tobias M. Hohl, Juan R. Cubillos-Ruiz
Deepika Awasthi, Sahil Chopra, Byuri A. Cho, Alexander Emmanuelli, Tito A. Sandoval, Sung-Min Hwang, Chang-Suk Chae, Camilla Salvagno, Chen Tan, Liliana Vasquez-Urbina, Jose J. Fernandez Rodriguez, Sara F. Santagostino, Takao Iwawaki, E. Alfonso Romero-Sandoval, Mariano Sanchez Crespo, Diana K. Morales, Iliyan D. Iliev, Tobias M. Hohl, Juan R. Cubillos-Ruiz
View: Text | PDF
Research Article Immunology Infectious disease

Inflammatory ER stress responses dictate the immunopathogenic progression of systemic candidiasis

Abstract

Recognition of pathogen-associated molecular patterns can trigger the inositol-requiring enzyme 1 α (IRE1α) arm of the endoplasmic reticulum (ER) stress response in innate immune cells. This process maintains ER homeostasis and also coordinates diverse immunomodulatory programs during bacterial and viral infections. However, the role of innate IRE1α signaling in response to fungal pathogens remains elusive. Here, we report that systemic infection with the human opportunistic fungal pathogen Candida albicans induced proinflammatory IRE1α hyperactivation in myeloid cells that led to fatal kidney immunopathology. Mechanistically, simultaneous activation of the TLR/IL-1R adaptor protein MyD88 and the C-type lectin receptor dectin-1 by C. albicans induced NADPH oxidase–driven generation of ROS, which caused ER stress and IRE1α-dependent overexpression of key inflammatory mediators such as IL-1β, IL-6, chemokine (C-C motif) ligand 5 (CCL5), prostaglandin E2 (PGE2), and TNF-α. Selective ablation of IRE1α in leukocytes, or treatment with an IRE1α pharmacological inhibitor, mitigated kidney inflammation and prolonged the survival of mice with systemic C. albicans infection. Therefore, controlling IRE1α hyperactivation may be useful for impeding the immunopathogenic progression of disseminated candidiasis.

Authors

Deepika Awasthi, Sahil Chopra, Byuri A. Cho, Alexander Emmanuelli, Tito A. Sandoval, Sung-Min Hwang, Chang-Suk Chae, Camilla Salvagno, Chen Tan, Liliana Vasquez-Urbina, Jose J. Fernandez Rodriguez, Sara F. Santagostino, Takao Iwawaki, E. Alfonso Romero-Sandoval, Mariano Sanchez Crespo, Diana K. Morales, Iliyan D. Iliev, Tobias M. Hohl, Juan R. Cubillos-Ruiz

×

Figure 2

Molecular pathways mediating IRE1α activation in C. albicans–exposed neutrophils.

Options: View larger image (or click on image) Download as PowerPoint
Molecular pathways mediating IRE1α activation in C. albicans–exposed neu...
(A and B) Bone marrow–resident neutrophils isolated from WT C57BL/6J mice (n = 4) were stimulated with HKCA or zymosan for 6 hours as indicated. Intracellular protein aggregates were assessed via ThT staining. Representative histograms and bar graphs for HKCA (A) and zymosan (B) are shown. (C) Neutrophils were exposed to vehicle control (Untreated), LPS (100 ng/mL), zymosan (25 μg/mL), or live C. albicans (MOI = 10) for 6 hours, and Xbp1 splicing was assessed by conventional RT-PCR. Xbp1u, unspliced form; Xbp1s, spliced form. Data are representative of at least 3 independent experiments with similar results. (D and E) Bone marrow neutrophils from WT C57BL/6J mice (n = 4) were stimulated with HKCA (MOI = 1) or zymosan (25 μg/mL) for 6 hours, and expression of the indicated transcripts was determined by RT-qPCR. (F and G) Bone marrow–resident neutrophils were isolated from mice of the indicated genotypes (n = 4/genotype) and stimulated for 6 hours with HKCA (MOI = 10) or zymosan (25 μg/mL). (H–M) Bone marrow–resident neutrophils from WT C57BL/6J mice (n = 3–4) were pretreated with the indicated inhibitors and stimulated for 6 hours as described in Methods. (F–M) Xbp1s levels were determined using RT-qPCR, and data were normalized to endogenous Actb. Data are shown as the mean ± SEM (A–G) or violin plots (H–M). Data are representative of 3–4 independent experiments with similar results. *P < 0.05, **P < 0.005, ***P < 0.0005, and ****P < 0.0001, by 1-way ANOVA with Dunnett’s multiple-comparison test (A and B), 2-tailed Student’s t test (D and E), 2-way ANOVA with Šídák’s multiple-comparison test (G), and 1-way ANOVA with Tukey’s test (F and H–M).