TRAIL-R1 is a negative regulator of pro-inflammatory responses and modulates long-term sequelae resulting from Chlamydia trachomatis infections in humans.
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 L2, or the murine pathogen C. muridarum, led to higher levels of MIP2 mRNA expression or IL-1β 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.
Department of Molecular Cell Biology, and Health Sciences Research Institute, University of California Merced, Merced, California, United States of America.
Mufadhal
M
Al-Kuhlani
James
J
Rothschild
Center for Immunobiology and Vaccine Development, Children's Hospital Oakland Research Institute, Oakland, California, United States of America.
James
J
Rothchild
Department of Pathology and Laboratory Medicine, University of California Irvine, Irvine, California, United States of America.
Sukumar
S
Pal
Department of Pathology and Laboratory Medicine, University of California Irvine, Irvine, California, United States of America.
Luis M
LM
de la Maza
Laboratory of Immunogenetics, Medical Microbiology and Infection Prevention, Research School V-ICI, VU University Medical Center, Amsterdam, The Netherlands.
Sander
S
Ouburg
Laboratory of Immunogenetics, Medical Microbiology and Infection Prevention, Research School V-ICI, VU University Medical Center, Amsterdam, The Netherlands; Institute of Public Health Genomics, Department of Genetics and Cell Biology, Research School GROW, University of Maastricht, Maastricht, The Netherlands.
Servaas A
SA
Morré
Center for Immunobiology and Vaccine Development, Children's Hospital Oakland Research Institute, Oakland, California, United States of America; Graduate Program in Bioengineering, University of California, Berkeley and San Francisco, California, United States of America; Department of Medicine, University of California San Francisco, San Francisco, California, United States of America.
Deborah
D
Dean
Department of Molecular Cell Biology, and Health Sciences Research Institute, University of California Merced, Merced, California, United States of America.
David M
DM
Ojcius
D000293:Adolescent; D000328:Adult; D000818:Animals; D002690:Chlamydia Infections / Q000235:genetics* / Q000276:immunology / Q000378:metabolism; D002692:Chlamydia trachomatis; D005260:Female; D005347:Fibroblasts / Q000378:metabolism; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006801:Humans; D007113:Immunity, Innate / Q000235:genetics; D007249:Inflammation / Q000235:genetics* / Q000276:immunology / Q000378:metabolism; D008168:Lung / Q000276:immunology / Q000378:metabolism; D008264:Macrophages / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand / Q000235:genetics* / Q000378:metabolism; D055815:Young Adult
D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand