New York City—April 13, 2010
“This is the first study to link this pathway to rheumatoid arthritis. In the twenty years or so that I have been studying regulation of inflammation, this seems to be the most potent inhibitory mechanism that we have seen,” said Lionel Ivashkiv, M.D., associate chief scientific officer at Hospital for Special Surgery in New York City and lead author of the study that has appeared online ahead of print.
For several years, Dr. Ivashkiv’s lab has been studying what regulates the production of cytokines in inflammatory diseases. Cytokines are small proteins that regulate inflammation; some cytokines spark inflammation and some cytokines are anti-inflammatory. By identifying pathways involved in cytokine production, the researchers hope to open up new therapeutic avenues for diseases such as arthritis in which cytokine production does not work properly.
Prior to this study, researchers knew that so-called immunoreceptor tyrosine-based activation motif ( ITAM)-coupled receptors were involved in regulating inflammation, but they did not know how the ITAM pathways actually turned off inflammatory signaling. Previous studies had shown that the ITAM pathway signaling components directly suppressed so-called Toll-like receptor signaling molecules involved in inflammation, but there was a hint that an alternative pathway may also be involved. The researchers thought that maybe the ITAM pathway might be involved in triggering another pathway that then inhibits inflammation.
In studies using white blood cells similar to those that cause disease, the researchers set out to investigate what signaling pathways might be induced by the activation of ITAM-associated receptors. They used fibrin(ogen) and immune complexes, proteins that are highly expressed at inflammatory sites, to activate the ITAM-associated receptors and then watched what happened. The researchers found that activation of the ITAM receptor set off a pathway known as DAP12-Syk-Pyk2-p38-MSK that was dependent on calcium signaling and discouraged pro-inflammatory cytokine production.
They also found that ITAM receptors induce IL-10, an anti-inflammatory cytokine, and proteins SOCS3, ABIN-3, A20, and Hes1 that have been implicated in the suppression of cytokines.
In other studies, they showed that this ITAM inhibitory pathway does not work properly in people with inflammatory arthritis.
“When we looked at macrophages from patients with arthritis, we found that the whole inhibitory pathway would not work,” Dr. Ivashkiv said. “What this study suggests is that one of the things that contributes to inflammation in arthritis is crippling of beneficial pathways that usually serve to turn inflammation off.” He said clinicians in the future may be able to focus on therapies that will augment or reinstitute these beneficial or homeostatic pathways as a way of turning off inflammation in chronic arthritis.
“Before this study we knew that ITAM-coupled receptors had the potential to inhibit inflammatory cytokine production, but there was very limited knowledge about how that worked,” Dr. Ivashkiv said. “What we accomplished with the study is that we have increased our understanding of an indirect inhibitory mechanism that we think can serve as the basis for designing new approaches to therapy. This work implicates for the first time a negative role for calcium signaling downstream of these ITAM-coupled receptors and explains how that works,”
He added that investigators believe that there is extensive crosstalk among the various pathways and they think that the ITAM receptors play a very important role in deciding how all the signaling gets integrated. “In terms of the homeostatic pathways that control inflammation, we think that this pathway that we have described is one of the strongest ones. It completely turns things off,” Dr. Ivashkiv said. “What you usually see are these partial inhibitions or attenuations in terms of inflammatory cytokine production. What we saw was a complete inhibition of the response.”
Dr. Ivashkiv said future work would focus on further elucidating molecular details of the pathway and further testing of its importance in arthritis and animal models of disease.
The work was funded by grants from the National Institutes of Health. Other authors of the study include Lu Wang, Ph.D., Rachael Gordon, Linda Huynh, Xiaodi Su, Kyung-Hyun Park Min, M.D., and George D. Kalliolias, M.D., from Hospital for Special Surgery; Jiahuai Han, Ph.D., from the Scripps Research Institute in La Jolla, Calif.; and J. Simon Arthur, M.D., from the MRC Protein Phosphorylation Unit, University of Dundee in Dundee, Scotland.
About HSS | Hospital for Special Surgery
HSS is the world’s leading academic medical center focused on musculoskeletal health. At its core is Hospital for Special Surgery, nationally ranked No. 1 in orthopedics (for the eighth consecutive year) and No. 3 in rheumatology by U.S. News & World Report (2017-2018). Founded in 1863, the Hospital has one of the lowest infection rates in the country and was the first in New York State to receive Magnet Recognition for Excellence in Nursing Service from the American Nurses Credentialing Center four consecutive times. The global standard total knee replacement was developed at HSS in 1969. An affiliate of Weill Cornell Medical College, HSS has a main campus in New York City and facilities in New Jersey, Connecticut and in the Long Island and Westchester County regions of New York State. In 2017 HSS provided care to 135,000 patients and performed more than 32,000 surgical procedures. People from all 50 U.S. states and 80 countries travelled to receive care at HSS. In addition to patient care, HSS leads the field in research, innovation and education. The HSS Research Institute comprises 20 laboratories and 300 staff members focused on leading the advancement of musculoskeletal health through prevention of degeneration, tissue repair and tissue regeneration. The HSS Global Innovation Institute was formed in 2016 to realize the potential of new drugs, therapeutics and devices. The culture of innovation is accelerating at HSS as 130 new idea submissions were made to the Global Innovation Institute in 2017 (almost 3x the submissions in 2015). The HSS Education Institute is the world’s leading provider of education on the topic on musculoskeletal health, with its online learning platform offering more than 600 courses to more than 21,000 medical professional members worldwide. Through HSS Global Ventures, the institution is collaborating with medical centers and other organizations to advance the quality and value of musculoskeletal care and to make world-class HSS care more widely accessible nationally and internationally.