Arthritis & Rheumatism, Volume 62,
November 2010 Abstract Supplement

Abstracts of the American College of
Rheumatology/Association of Rheumatology Health Professionals
Annual Scientific Meeting
Atlanta, Georgia November 6-11, 2010.

Identifying the TLR4 Bearing Target Cell in Experimental Arthritis.

van den Brand,  Ben T., Abdollahi-Roodsaz,  Shahla, Bennink,  Miranda B., Arntz,  Onno J., van den Berg,  Wim B., van de Loo,  Fons A. J.


The IL-1 receptor antagonist (IL-1Ra) knockout mice spontaneously develop T-cell driven arthritis due to excessive IL-1 signalling. Joint destruction is accompanied by increased Th17 cells and elevated IL-17 levels compared to wild type (Balb/c) mice. When cross bred with TLR4 knock out (TLR4-/-) these animals showed reduced inflammation, joint destruction, and diminished IL-17 levels. To reduce adverse effects of TLR4 inhibition a cell specific targeted therapy of arthritis is desired. Therefore, we set out to identify the TLR4 bearing cells in experimental arthritis responsible for increased IL-17 production and arthritis severity.


A reciprocal sex-mismatched bone marrow transplantation was performed with TLR4-/- and TLR4+/+ mice in the IL-1Ra-/- background and Balb/c bone marrow as control. Y-chromosome staining of bone marrow was performed to assess engraftment. Clinical manifestation of disease was assessed macroscopically over time. Spleen and lymph node cells were isolated and subjected to T-helper subset analysis.


Engraftment of bone marrow was near 100% successful as determined by Y-chromosome staining of the bone marrow, which indicates a successful reconstitution. Lack of TLR4 on either the engrafted bone marrow cells or the radio-resistant cells in the joint did not affect disease incidence. However, animals that lacked TLR4 on the engrafted bone marrow derived cells, radio-resistant cells, or both showed reduced macroscopic arthritis scores. In mesenteric lymph nodes there were no differences observed in percentage of IFNg and IL-17 producing cells. Neither was there a difference in Th1 cells in the spleen. However, decreased Th17 levels were observed in the spleen when radio-resistant cells lack TLR4.


These data suggest that TLR4 plays a role on both the bone marrow derived and local resident cells in aggravating experimental arthritis. TLR4 plays a role locally on the synovial fibroblasts by creating a more aggressive inflammatory environment in the joint cavity and thereby increasing joint destruction. Conversely, TLR4 activation on the bone marrow derived cells could increase T-cell activation by antigen presenting cells and thereby promoting a more aggressive Th17 phenotype and increase joint swelling.

To cite this abstract, please use the following information:
van den Brand, Ben T., Abdollahi-Roodsaz, Shahla, Bennink, Miranda B., Arntz, Onno J., van den Berg, Wim B., van de Loo, Fons A. J.; Identifying the TLR4 Bearing Target Cell in Experimental Arthritis. [abstract]. Arthritis Rheum 2010;62 Suppl 10 :713
DOI: 10.1002/art.28481

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