RNA recognition by human TLR8 can lead to autoimmune inflammation

Cristiana Guiducci, Mei Gong, Alma Martina Cepika, Zhaohui Xu, Claudio Tripodo, Lynda Bennett, Chad Crain, Pierre Quartier, John J. Cush, Virginia Pascual, Robert L. Coffman, Franck J. Barrat

Research output: Contribution to journalArticle

71 Citations (Scopus)

Abstract

Studies on the role of the RNA receptor TLR8 in inflammation have been limited by its different function in human versus rodents. We have generated multiple lines of transgenic mice expressing different levels of human TLR8. The high copy number chimeras were unable to pass germline; developed severe inflammation targeting the pancreas, salivary glands, and joints; and the severity of the specific phenotypes closely correlated with the huTLR8 expression levels. Mice with relatively low expression levels survived and bred successfully but had increased susceptibility to collagen-induced arthritis, and the levels of huTLR8 correlated with proinflammatory cytokines in the joints of the animals. At the cellular level, huTLR8 signaling exerted a DC-intrinsic effect leading to up-regulation of co-stimulatory molecules and subsequent T cell activation. A pathogenic role for TLR8 in human diseases was suggested by its increased expression in patients with systemic arthritis and the correlation of TLR8 expression with the elevation of IL-1b levels and disease status. We found that the consequence of self-recognition via TLR8 results in a constellation of diseases, strikingly distinct from those related to TLR7 signaling, and points to specific inflammatory diseases that may benefit from inhibition of TLR8 in humans.

Original languageEnglish (US)
Pages (from-to)2903-2919
Number of pages17
JournalJournal of Experimental Medicine
Volume210
Issue number13
DOIs
StatePublished - Dec 1 2013
Externally publishedYes

Fingerprint

RNA
Inflammation
Toll-Like Receptor 8
Joints
Experimental Arthritis
Salivary Glands
Transgenic Mice
Arthritis
Pancreas
Rodentia
Up-Regulation
Cytokines
T-Lymphocytes
Phenotype

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

Cite this

Guiducci, C., Gong, M., Cepika, A. M., Xu, Z., Tripodo, C., Bennett, L., ... Barrat, F. J. (2013). RNA recognition by human TLR8 can lead to autoimmune inflammation. Journal of Experimental Medicine, 210(13), 2903-2919. https://doi.org/10.1084/jem.20131044

RNA recognition by human TLR8 can lead to autoimmune inflammation. / Guiducci, Cristiana; Gong, Mei; Cepika, Alma Martina; Xu, Zhaohui; Tripodo, Claudio; Bennett, Lynda; Crain, Chad; Quartier, Pierre; Cush, John J.; Pascual, Virginia; Coffman, Robert L.; Barrat, Franck J.

In: Journal of Experimental Medicine, Vol. 210, No. 13, 01.12.2013, p. 2903-2919.

Research output: Contribution to journalArticle

Guiducci, C, Gong, M, Cepika, AM, Xu, Z, Tripodo, C, Bennett, L, Crain, C, Quartier, P, Cush, JJ, Pascual, V, Coffman, RL & Barrat, FJ 2013, 'RNA recognition by human TLR8 can lead to autoimmune inflammation', Journal of Experimental Medicine, vol. 210, no. 13, pp. 2903-2919. https://doi.org/10.1084/jem.20131044
Guiducci, Cristiana ; Gong, Mei ; Cepika, Alma Martina ; Xu, Zhaohui ; Tripodo, Claudio ; Bennett, Lynda ; Crain, Chad ; Quartier, Pierre ; Cush, John J. ; Pascual, Virginia ; Coffman, Robert L. ; Barrat, Franck J. / RNA recognition by human TLR8 can lead to autoimmune inflammation. In: Journal of Experimental Medicine. 2013 ; Vol. 210, No. 13. pp. 2903-2919.
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