|M.Sc Student||Gelfand Anat|
|Subject||The Role of the Chemokine CCL1 in the Regulation|
of the Immune Response
|Department||Department of Medicine||Supervisor||Professor Nathan Karin|
|Full Thesis text|
Inflammatory bowel diseases are immune mediated idiopathic disorders of the gastrointestinal track. The etiology is poorly understood but thought to involve dysregulated immune response associated with loss of tolerance to the gut flora. Given the destructive nature of cellular infiltrates in the intestinal mucosa during IBD, many studies have focused on the importance of recruitment factors, such as chemokines, in the development of the disease.
Chemokines are a group of structurally related chemotactic cytokines shown to mediate leukocyte migration to specific organs or inflammatory sites. Chemokines exert their effect through chemokine receptors, which belong to a family of 7- transmembrane G-coupled receptors.
The CC chemokine ligand 1 (CCL1) is known to be produced by activated monocytes, T lymphocytes and endothelial cells. CCL1 exclusively activates CCR8, and CCR8 transfected cells migrate toward CCL1 in a dose dependent manner. CCR8 is believed to mediate a broad range of cellular activities including TH2 and T regulatory cell recruitment in allergic inflammation. Recently, CCL1 was shown to be highly regulated in Treg cells its neutralization both inhibited Treg conversion and suppressive function.
Previous studies in our lab demonstrated that CCL1 potentiates Foxp3 Tregs suppressive function and that administration of CCL1- Ig ameliorated ongoing EAE in mice . In this study, we used CCR8 KO mice to examine the role of CCR8- CCL1 axis in the development of experimental colitis emphasis on its effects on Treg cells function.
We used the DSS model to chemically induce experimental colitis and monitored disease development. Interestingly, compared to WT mice, CCR8 deficient mice exhibited exacerbated response to DSS-treatment. The clinical signs associated with DSS-treatment, including weight loss, diarrhea and rectal bleeding, appeared earlier in CCR8 KO mice and resulted in markedly increased disease severity, as shown by the histopathological tissue damage. CCL1-Ig treatment of DSS-challenged mice revealed a potential immunomodulatory role of CCL1 during colonic inflammation. While CCR8 KO mice were unaffected, DSS-challenged WT mice injected with CCL1-Ig showed attenuated clinical signs and marked reduction in colonic pathology.
Given the crucial role of Treg cells in the maintenance of self-tolerance and the prevention of autoimmune disease we sought to examine whether the exacerbated response of CCR8 KO mice to DSS-treatment is mediated through impaired Treg cells function. Treg cells were shown to prevent and treat established colitis. We here demonstrate that while WT Treg cells alleviated clinical symptoms and histopathological damage, CCR8-/- Treg transfer was inefficient and did not altered disease course. We additionally evaluated the effect of CCL1 stimuli on WT Tregs function. Our results demonstrated that Foxp3 Treg cells isolated from CCL1-Ig treated donor were more efficient in attenuating colitis development.
Collectively we demonstrate the crucial role of CCR8- CCL1 axis for controlling intestinal inflammation in particular for Treg cells suppressive function in vivo. We showed that CCR8 KO mice were more susceptible to DSS-induced colitis and that CCR8-/- Treg cell failed to suppress colitis development. We additionally revealed an anti- inflammatory effect of CCL1 administration on colitis initiation and severity making the CCR8-CCL1 axis a target for immunomodulation.