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.

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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/