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Abstract Number: 1441

Dendritic Cell-Specific Transmembrane Protein (DC-STAMP) Knockout Attenuates Arthritis Progression and Systemic Inflammation in TNF-Tg Arthritis Mouse Models

Yahui Grace Chiu1, Richard Bell2, Dongge Li3, Edward Schwarz4 and Christopher T. Ritchlin5, 1Allergy, Immunology, and Rheumatology, University of Rochester Medical Center, Rochester, NY, 2Pathology, University of Rochester, Rochester, NY, 3Allergy, Immunology and Rheumatology, University of Rochester, Rochester, NY, 4Orthopedeatrics, University of Rochester, Rochester, NY, 5Allergy Immunology & Rheumatology, University of Rochester Medical Center, Rochester, NY

Meeting: 2016 ACR/ARHP Annual Meeting

Date of first publication: September 28, 2016

Keywords: Arthritis, Inflammation, Lung, mouse model and tumor necrosis factor (TNF)

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Session Information

Date: Monday, November 14, 2016

Session Title: Rheumatoid Arthritis – Animal Models - Poster II

Session Type: ACR Poster Session B

Session Time: 9:00AM-11:00AM

Background/Purpose: Tumor necrosis factor-transgenic (TNF-Tg) mice develop systemic inflammatory polyarthritis. DC-STAMP, a multi-pass transmembrane protein, was originally identified from a dendritic cell library and required for cell-cell fusion between osteoclast precursors (OCPs). To examine if DC-STAMP also regulates inflammatory responses in TNFα-mediated arthritis pathogenesis, we introduced a DC-STAMP null mutation into the TNF-Tg background and examined immune responses and inflammatory-erosive arthritis progression in the presence or absence of DC-STAMP.

Methods: Two TNF-Tg lines (TNF-Tg3647 & Taconic 1006) were crossed to DC-STAMP-/- mice to generate distinct DC-STAMP genotypes (+/+, +/-, and -/-) under TNF-Tg (+ or -) background. Arthritis progression was evaluated by grip strength monthly until mice reached 4 months of age. Immune responses were evaluated by flow cytometry on cells obtained from the ascites of 4-month old mice. ELISA was performed to assess endogenous mouse and transgenic human TNF levels in sera. Immunohistochemistry (IHC) were performed to identify DC-STAMP+ cells in lung, heart and intestine.

Results: We observed the following:(1) Synthetic lethality in Taconic 1006: no live DC-STAMP-/-TNF+ pups were detected; (2) In TNF-Tg3647 background: although the majority of DC-STAMP-/-TNF+ pups died within a week after birth, several DC-STAMP-/-TNF+ pups survived; (3) In contrast to their DC-STAMP+/-TNF+ & DC-STAMP+/+TNF+ littermates where widespread inflammation (ascites, heart & lung pathology) and arthritis progression were observed, DC-STAMP-/- TNF-Tg+ mice showed attenuated joint pathology and inflammation. The grip strength of DC-STAMP+/-TNF+ & DC-STAMP+/+TNF+ mice decreased dramatically between weeks 11 & 12 (0.6±0.2N), whereas DC-STAMP-/-TNF+ mice grip strength was relatively strong at week 12 (1.6±0.3N), p=0.05 between 2 groups; (4) The protective effect of DC-STAMP null mutation on TNFα-induced arthritis progression and inflammation was independent of TNFα serum levels. Intriguingly, a higher serum TNFα level was detected in arthritis-free DC-STAMP-/-TNF+ mice compared to DC-STAMP+/+ TNF+ littermates with severe arthritis; (5) 65% of cells collected from inflammatory ascites were DC-STAMP+CD11b+ cells; (6) the lung, heart and intestine of DC-STAMP-/-Tg+ mice showed significantly less inflammation (neutrophils & CD11b+ monocytes infiltration) and attenuated pathology than their DC-STAMP+/+Tg+ littermates.

Conclusion: The absence of DC-STAMP expression in the TNFα-overexpressing mouse arthritis model was associated with suppression of both systemic inflammation and arthritis progression. The presence of DC-STAMP+ cells in ascitic fluid coupled with attenuated arthritis and systemic inflammation in DC-STAMP -/- mice provides preliminary evidence that DC-STAMP is involved in the regulation of TNF-induced immune responses. Examination of the molecular mechanism underlying the altered immune system and anti-inflammatory responses in DC-STAMP-/-TNF+ mice will provide new insights into the interplay between DC-STAMP and TNFα. Collectively, our results suggest that blockade of DC-STAMP may serve as an effective therapy for arthritis medication.


Disclosure: Y. G. Chiu, None; R. Bell, None; D. Li, None; E. Schwarz, None; C. T. Ritchlin, Amgen, Janssen Pharmaceutica Product, L.P., and UCB, 2,AbbVie, Amgen, Janssen Pharmaceutica Product, L.P., Regeneron, and UCB, 5.

To cite this abstract in AMA style:

Chiu YG, Bell R, Li D, Schwarz E, Ritchlin CT. Dendritic Cell-Specific Transmembrane Protein (DC-STAMP) Knockout Attenuates Arthritis Progression and Systemic Inflammation in TNF-Tg Arthritis Mouse Models [abstract]. Arthritis Rheumatol. 2016; 68 (suppl 10). https://acrabstracts.org/abstract/dendritic-cell-specific-transmembrane-protein-dc-stamp-knockout-attenuates-arthritis-progression-and-systemic-inflammation-in-tnf-tg-arthritis-mouse-models/. Accessed March 1, 2021.
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ACR Meeting Abstracts - https://acrabstracts.org/abstract/dendritic-cell-specific-transmembrane-protein-dc-stamp-knockout-attenuates-arthritis-progression-and-systemic-inflammation-in-tnf-tg-arthritis-mouse-models/

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