1. Neuro-immun interactions that regulate the pathogenesis of inflammatory diseases
Regional neural activation defines a gateway for autoreactive T cells to cross the blood-brain barrier
Although it is believed that neural activations can affect immune responses, very little is known about the neuro-immune interactions involved, especially the key regulators for immune signals to reach from the blood to the CNS. We here describe dorsal blood vessels in the 5th lumbar-cord that show excess chemokine levels in a manner dependent on regional neural activations of the soleus-muscle. These responses appear to act as a gate for blood cell populations including immune cells to enter the CNS. This gate can promote pathogenic T cells inflammatory inflow, which risks autoimmune diseases like multiple sclerosis. Therefore, these regional neuro-immune interactions may offer new therapeutic targets for neurological diseases.
Arima Y., M. Harada, D. Kamimura, J-H. Park, F. Kawano, F. E. Yull, T. Kawamoto, Y. Iwakura, U.A.K. Betz, G. Márquez, T. S. Blackwell, Y. Ohira, T. Hirano, and M. Murakami.
Regional Neural Activation Defines a Gateway for Autoreactive T Cells to Cross the Blood-Brain Barrier.
Cell.148: 447-457, 2012 (Cell) (PubMed) (Cell Previews)
2. Inflammation amplifer: a molecular mechanism that promotes chronic inflammation
Disease-Association Analysis of an Inflammation-Related Feedback Loop
The IL-6-triggered positive feedback loop for NFkB signaling (or the inflammation amplifier) was originally discovered as a synergistic-activation signal that follows IL-17/IL-6 stimulation in nonimmune cells. Subsequent results from animal models have shown that the amplifier is activated by stimulation of NFkB and STAT3 and induces chemokines and inflammation via an NFkB loop. However, its role in human diseases is unclear. Here, we combined two genome-wide mouse screens with SNP-based disease association studies, revealing 1,700 genes related to the inflammation amplifier, 202 of which showed 492 indications of association with ailments beyond autoimmune diseases. We followed up on ErbB1 from our list. Blocking ErbB1 signaling suppressed the inflammation amplifier, whereas the expression of epiregulin, an ErbB1 ligand, was higher in patients with inflammatory diseases. These results indicate that the inflammation amplifier is indeed associated with human diseases and disorders and that the identified genes may make for potential therapeutic targets.
Masaaki Murakami*#, Masaya Harada*, Daisuke Kamimura*, Hideki Ogura, Yuko Okuyama, Noriko Kumai, Azusa Okuyama, Rajeev Singh, Jing-Jing Jiang, Toru Atsumi, Sayaka Shiraya, Yuji Nakatsuji, Makoto Kinoshita, Hitoshi Kohsaka, Makoto Nishida, Saburo Sakoda, Nobuyuki Miyasaka, Keiko Yamauchi-Takihara, and Toshio Hirano# (*, equal contribution; #, correspondence)
Disease-Association Analysis of an Inflammation-Related Feedback Loop.
Cell Reports.3: 946-959, 2013 (PubMed)