Understanding how the different members of the immune system work together to protect us against disease, and how deregulated immune responses lead to pathology have a strong impact in public health. Intense research over the last years has increased the understanding of the genetic as well as environmental factors determining the development and function of the different ILC subsets. The important role of ILCs at the initiation of immune response offers the possibility of new approaches for immunotherapy, in particular targeting pathologies at mucosal surfaces. For instance, by enhancing the function of specific ILC subsets participating in type 1 immunity to viruses, intracellular bacteria and tumors, type 2 immunity to helminths, also promoting tissue repair and regulating metabolism of adipose tissue, or type 3 immunity to extracellular microbes could be strengthened. Various already available drugs that target inducer or effector cytokines of type 1, 2 or 3 immune responses such as recombinant IFN-γ, GM-CSF and IL-22 proteins as well as neutralizing antibodies against most effector cytokines could be used locally and early during immune responses to primarily affect ILCs or block their activity. However, the principal challenge is the identification of specific activators and suppressors of the different ILC subsets and compounds avoiding systemic deregulation of immune function during homeostasis and disease. In this regard, characterization of zebrafish ILCs will allow exploiting the advantages of this model (small size, cheap maintenance, large offspring, fast grow rate, transparency of embryos and ex utero development) to perform screening for molecules, genes and gene regulatory regions controlling ILC function. In addition the simplicity of targeted genome editing using the CRISPR/Cas9 system in zebrafish will make possible to quickly generate zebrafish lines affecting ILC function.
Studies about the pathogenesis of numerous diseases indicate that enhanced antimicrobial defense, resistance against damage and tissue regeneration might be beneficial in several disorders. In this regard, it has been proposed that reinforcement of the activity of IL-22 might have a favorable impact in inflammatory bowel disease, graft‐versus‐host disease (GvHD), pancreas and alcoholic liver injury, and organ transplantation. On the other hand, attenuation of IL-22 action would be beneficial in psoriasis and certain cancers, where differentiation, proliferation and inflammation play a detrimental role. As IL‐22 does not target immune cells, its modulation might not lead to immune‐related side effects occurring when targeting cytokines such as type I interferons (IFNs) or tumor necrosis factors (TNFs). Therefore, producing short and long term modulators of IL-22 function, which could be used locally or systemically depending on the pathological context, will be beneficial for the treatment of several diseases. In this regard, we are currently collaborating to use our il22:mCherry reporter zebrafish line to perform screening of genes and molecules modulating intestinal inflammation and to study IBD-risk genes with unknown function.
