According to a new study, small proteins, called chemokines, that direct immune cells toward sites of infection can also form DNA-bound nanoparticles that can induce chronic, dysfunctional immune responses. The surprising discovery of this new activity for this well-studied class of immune signalling molecules could shed light on some types of immune disorders. The study, published 31 May in the Journal of Experimental Medicine, reveals an entirely new mode of triggering the immune system, through which chemokine-DNA nanoparticles can induce inflammation. Results in preclinical models suggest that this mechanism may play a central role in autoimmune diseases such as scleroderma and lupus. The work was part of the scientists’ ongoing efforts to understand scleroderma, an autoimmune condition that causes inflammation and hardening of the skin. “We had a project looking at scleroderma, and it was shown by us and others a few years ago that patients with this condition have an elevated level of the chemokine CXCL4 in their blood,” said senior author Dr. Franck Barrat, professor of microbiology and immunology at Weill Cornell Medicine and the Michael Bloomberg Chair and senior scientist at HSS. But the role of this chemokine in disease is unclear, and we didn’t expect the chemokine to provoke this particular immune response.
In setting up controls for one of their experiments, Dr. Barrat’s team, including the first author, Dr. Yong Du, a postdoctoral associate in microbiology and immunology at Weill Cornell Medicine and a member of the HSS Research Institute, discovered that CXCL4 and several other chemokines could induce immune cells called plasmacytoid dendritic cells (pDCs) to produce interferon-alpha. Surprisingly, the induction appeared to be independent of known chemokine receptors, indicating that these molecules were activating the immune cells through some previously unknown mechanism.
Subsequent experiments revealed that the chemokines can bind pieces of DNA to form nanoparticles, which then bypass the cells’ chemokine receptors to induce interferon production directly. Tests in mouse models of skin inflammation suggest that this mechanism could account for the chronic immune activation that underlies scleroderma and other autoimmune diseases.