According to a new study, small proteins called chemokines that drive immune cells toward areas of infection can also generate DNA-bound nanoparticles that can trigger persistent, dysfunctional immune responses.
The unexpected finding of this novel action for this well-studied family of immune signalling molecules may shed light on some immunological diseases. The research, which was published on May 31 in the Journal of Experimental Medicine, offers an altogether new way for chemokine-DNA nanoparticles to activate the immune system. Preclinical model results imply that this process is important in autoimmune disorders like scleroderma and lupus.
The research was part of the scientists’ continuous attempts to learn more about scleroderma, an inflammatory disorder that involves skin inflammation and stiffening. “A few years ago, we and others showed 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. “However, the relevance of this chemokine in illness is unknown, and we did not expect the chemokine to elicit this specific immune response.”
Dr. Barrat’s team, which included 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 plasmacytoid dendritic cells (pDCs) to produce interferon-alpha. Surprisingly, the induction appeared to be independent of recognised chemokine receptors, indicating that these chemicals were activating immune cells via an undiscovered method.
Subsequent research found that chemokines may attach fragments of DNA to produce nanoparticles, which then circumvent the chemokine receptors in cells to directly activate interferon production.
Experiments in skin inflammation animal models show that this process might explain the persistent immune activation that underpins scleroderma and other autoimmune disorders. The findings also show that distinct DNA-chemokine nanoparticles may be at the root of various disorders. While CXCL4 appears to be crucial in scleroderma, another chemokine, CXCL10, may play a similar role in lupus.
Dr. Barrat believes that DNA-chemokine nanoparticles are an important component of the body’s wound healing system. “Following a skin injury, such as a cut, dendritic cells penetrate the skin and generate an inflammatory milieu that allows the lesion to heal properly.
Our findings imply that these cells do not require the presence of a pathogen, such as a virus or bacteria, and may detect self-DNA directly “He stated. “And that inflammation is aiding in the recruitment of other immune system cells.” In autoimmune illness, the process goes wrong, resulting in a persistent inflammatory state that eventually destroys tissue rather than mending it.
The researchers also worked on a related study, which was published in Nature Communications on June 14th, and found that CXCL4 may cause a comparable inflammatory response in monocytes, another essential kind of immune cell. Taken together, the data suggest potential techniques for suppressing autoimmunity without interfering with normal immune responses.
“It informs you what kind of reaction you need to inhibit, not only at the DNA-chemokine level, but perhaps farther downstream in the cells themselves,” Dr. Barrat explained.