Inflammation is a double-edged sword ? it is the first line of defence for the immune system against infection. But long-lived immune reactions caused by damaged cells ? called sterile inflammation, can lead to chronic inflammation and diseases such as osteoarthritis, rheumatoid arthritis and fibrosis.
Scientists from inStem have found how sterile inflammation can develop and designed and tested a new drug delivery system to combat chronic inflammation.
Dr. Srikala Raghavan at the Centre for Inflammation and Tissue Homeostasis and her team studied how the loss of a protein called beta integrin 1 from skin cells can cause a wide-spread inflammatory reaction without the presence of invasive germs.
Beta integrin 1 is an essential protein on the cell surface that is involved in regulating cell shape, movement and cell reproduction. Dr. Srikala?s team found the loss of this molecule in the skin cells of mice resulted in a massive cascade of inflammatory signals that began to recruit large numbers of immune cells. These events eventually distort the skin?s basement membrane, the tough, flexible matrix to which skin cells are anchored. However, despite widespread disarray in the basement membrane, the skin barrier remains intact.
?What?s really unique about our model is that barrier formation is completely intact in our animals. But our animals still mount a strong immune response, suggesting that the source of the inflammatory response is not external,? said Dr. Srikala pointing out that this makes the system an ideal model to study sterile inflammation. ?Working out the inflammatory response from the loss of beta integrin 1 and then showing that we could alleviate this inflammation with drugs was really exciting.?
However, the immune reaction and inflammation in such mice begins to build up while they are still developing embryos in the mother. Therefore, treating the inflammation with drugs was a big challenge.
A collaborative effort with Praveen Vemula?s Lab of Self-Assembled Biomaterials and Translational Research, led to the development and testing of a new drug delivery system to combat chronic inflammation.
?We took up the challenge of developing a very localised drug delivery vehicle,? said Dr. Praveen Vemula. ?We needed to deliver the drugs transdermally, that is, into the skin.?
?Typically, cationic molecules ? those with a positive charge ? fuse with skin and can deliver cargoes inside skin. That is why we used a cationic lipid-based delivery system,? Dr. Vemula explained.� ?What really got us excited was the efficiency of the drug delivery. We were of course hoping it would work, but we expected only about 10 to 20% drug delivery. The efficiency was so high, that the outcomes of the drug treatment were plainly visible, which was a huge surprise.?
?Understanding the signals in sterile inflammation will be critical to developing targeted therapies for chronic inflammatory diseases like arthritis, Crohn?s disease and skin conditions like fibrosis,? said the lead authors of the study, Ambika Kurbet and Samarth Hegde from Srikala?s team.
The results obtained by the study were published in the journal Cell Reports in its latest edition.