TRAIL-R1 Is a Negative Regulator of Pro-Inflammatory Responses and Modulates Long-Term Sequelae Resulting from Chlamydia trachomatis Infections in Humans

Mufadhal Al-Kuhlani, James Rothchild, Sukumar Pal, Luis M. de la Maza, Sander Ouburg, Servaas A. Morre, Deborah Dean, David M. Ojcius*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

Abstract

The immune system eliminates Chlamydia trachomatis infection through inflammation. However, uncontrolled inflammation can enhance pathology. In mice, TNF-related apoptosis-inducing ligand receptor (TRAIL-R), known for its effects on apoptosis, also regulates inflammation. In humans, the four homologues of TRAIL-R had never been investigated for effects on inflammation. Here, we examined whether TRAIL-R regulates inflammation during chlamydial infection. We examined TRAIL-R1 single nucleotide polymorphisms (SNPs) in an Ecuadorian cohort with and without C. trachomatis infections. There was a highly significant association for the TRAIL+626 homozygous mutant GG for infection vs no infection in this population. To confirm the results observed in the human population, primary lung fibroblasts and bone marrow-derived macrophages (BMDMs) were isolated from wildtype (WT) and TRAIL-R-deficient mice, and TRAIL-R1 levels in human cervical epithelial cells were depleted by RNA interference. Infection of BMDMs and primary lung fibroblasts with C. trachomatis strain L-2, or the murine pathogen C. muridarum, led to higher levels of MIP2 mRNA expression or IL-1 beta secretion from TRAIL-R-deficient cells than WT cells. Similarly, depletion of TRAIL-R1 expression in human epithelial cells resulted in a higher level of IL-8 mRNA expression and protein secretion during C. trachomatis infection. We conclude that human TRAIL-R1 SNPs and murine TRAIL-R modulate the innate immune response against chlamydial infection. This is the first evidence that human TRAIL-R1 is a negative regulator of inflammation and plays a role in modulating Chlamydia pathogenesis.
Original languageEnglish
Article numbere93939
JournalPLOS ONE
Volume9
Issue number4
DOIs
Publication statusPublished - 2 Apr 2014

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