Below the surface: The inner lives of TLR4 and TLR9.

TLRs are a class of pattern recognition receptors (PRRs) that detect invading microbes by recognizing pathogen-associated molecular patterns (PAMPs). Upon PAMP engagement, TLRs activate a signaling cascade that leads to the production of inflammatory mediators. The localization of TLRs, either on the plasma membrane or in the endolysosomal compartment, has been considered to be a fundamental aspect to determine to which ligands the receptors bind, and which transduction pathways are induced. However, new observations have challenged this view by identifying complex trafficking events that occur upon TLR-ligand binding. These findings have highlighted the central role that endocytosis and receptor trafficking play in the regulation of the innate immune response. Here, we review the TLR4 and TLR9 transduction pathways and the importance of their different subcellular localization during the inflammatory response. Finally, we discuss the implications of TLR9 subcellular localization in autoimmunity.

Granulin 1 Promotes Retinal Regeneration in Zebrafish.

Purpose: Retinal degenerative diseases can progress to severe reductions of vision. In general, the changes are permanent in higher vertebrates, including humans; however, retinal regeneration can occur in lower vertebrates, such as amphibians and teleost fish. Progranulin is a secreted growth factor that is involved in normal development and wound-healing processes. We have shown that progranulin promotes the proliferation of retinal precursor cells in mouse retinas. The purpose of this study was to investigate the role played by granulin 1 (grn1) in the retinal regeneration in zebrafish. Methods: We injured the retina of zebrafish with needle puncturing, and the retinas were examined at different times after the injury. We also checked the proliferation and the expression of retinal regeneration-related genes after knockdown of grn1 by electroporation with morpholino oligonucleotides (MO) and intravitreal injection of recombinant grn1. Results: Our results showed that the level of grn1 was highly increased after retinal injury, and it was expressed in various types of retinal cells. A knockdown of grn1 reduced the proliferation of Müller glial cells in zebrafish eyes undergoing retinal regeneration. The knockdown of grn1 also reduced the expression of achaete-scute homolog 1a (ascl1a), an important factor in retinal regeneration. An intravitreal injection of recombinant grn1 led to a proliferation of Müller glial cells and an increase in the expression of retinal regeneration-related genes, such as ascl1a and lin28. Conclusions: These findings suggested that grn1 should be considered as a target for stimulating the dedifferentiation of Müller glial cells and retinal regeneration.