Tuesday, 6 January 2015

Interleukin-34 affects blood brain barrier

Jin S, Sonobe Y, Kawanokuchi J, Horiuchi H, Cheng Y, Wang Y, Mizuno T, Takeuchi H, Suzumura A. Interleukin-34 Restores Blood-Brain Barrier Integrity by Upregulating Tight Junction Proteins in Endothelial Cells. PLoS One. 2014 Dec 23;9(12):e115981. doi: 10.1371/journal.pone.0115981. eCollection 2014

Interleukin-34 (IL-34) is a newly discovered cytokine as an additional ligand for colony stimulating factor-1 receptor (CSF1R), and its functions are expected to overlap with colony stimulating factor-1/macrophage-colony stimulating factor. We have previously shown that the IL-34 is primarily produced by neurons in the central nervous system (CNS) and induces proliferation and neuroprotective properties of microglia which express CSF1-R. However, the functions of IL-34 in the CNS are still elucidative. Here we show that CNS capillary endothelial cells also express CSF1R. IL-34 protected blood-brain barrier integrity by restored expression levels of tight junction proteins, which were downregulated by pro-inflammatory cytokines. The novel function of IL-34 on the blood-brain barrier may give us a clue for new therapeutic strategies in neuroinflammatory and neurodegenerative diseases.

Interleukin-34, or IL-34 is a protein belonging to a group of cytokines called interleukins.  The protein is composed of 241 amino acids, 39 kilodaltons in mass, and forms homodimers. IL-34 increases growth or survival of immune cells known as monocytes; it elicits its activity by binding the Colony stimulating factor 1 receptor.

Messenger RNA (mRNA) expression of human IL-34 is most abundant in spleen but occurs in several other tissues:thymus, liver, small intestine, colon, prostate gland, lung, heart, brain, kidney, testes, and ovary. The discovery of IL-34 protein in the red pulp of the spleen suggests involvement in growth and development of myeloid cells, consistent with its activity on monocytes. 

In this study they show that IL-34 is involved in blood vessel function.

Tight junctions are the closely associated areas of two cells whose membranes join together forming a virtually impermeable barrier to fluid. It is a type of junctional complex present only in vertebrates.

Tight junctions are composed of a branching network of sealing strands, each strand acting independently from the others. Therefore, the efficiency of the junction in preventing ion passage increases exponentially with the number of strands. Each strand is formed from a row of transmembrane proteins embedded in both plasma membranes, with extracellular domains joining one another directly. Although more proteins are present, the major types are the claudins and the occludins. These associate with different peripheral membrane proteins such as ZO-1 located on the intracellular side of plasma membrane, which anchor the strands to theactin component of the cytoskeleton. Thus, tight junctions join together the cytoskeletons of adjacent cells.

These help keep things out of the brain. During neuroinflammation these junctions get re-organised as cells pass through the blood vessel.

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