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
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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

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Figure 7

Pharmacological IRE1α inhibition controls kidney inflammation and extends survival in mice with systemic candidiasis.

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Pharmacological IRE1α inhibition controls kidney inflammation and extend...
(A) Bone marrow–resident neutrophils from WT C57BL/6J mice (n = 6) were isolated and pretreated for 1 hour with vehicle control or MKC8866 (2.5 μM), followed by stimulation with either zymosan (25 μg/mL) or HKCA (MOI = 10) for 6 hours. Xbp1s transcript levels were determined by RT-qPCR and normalized to endogenous Actb expression in each sample. (B–D) WT C57BL/6J mice (n = 8–10 per group) were infected i.v. via tail vein injection with 105 C. albicans cells. Twenty-four hours later, mice were treated once daily with vehicle control or MKC8866 (300 mg/kg) via oral gavage until postinfection day 5, and kidneys were resected 24 hours after the last treatment. Expression of the indicated transcripts was determined by RT-qPCR, and data were normalized to endogenous Actb expression in each sample. (E–J) Levels of the indicated proinflammatory factors were evaluated in the same kidney samples used in B–D. (K) WT C57BL/6J mice (n = 16 per group) were infected via tail vein injection with 105 C. albicans cells. After 24 hours, mice were treated once daily with vehicle control or MKC8866 (300 mg/kg) via oral gavage for up to 10 days, and host survival was monitored thereafter. Data are shown as the mean ± SEM. *P < 0.05, **P < 0.005, ***P < 0.0005, and ****P < 0.0001, by 1-way ANOVA with Tukey’s test (A), 2-tailed Student’s t test (B–J), and log-rank test (K).