Monthly Archives: May 2010

IL-33—a new treatment against sepsis?

New research shows that the novel cytokine interleukin (IL)-33 reduces sepsis and has “therapeutic potential” to treat this often fatal inflammatory condition. According to the study published this week in Nature Medicine, IL-33 promotes neutrophil recruitment to the site of infection, which is a critical host defence response, and the levels of the decoy IL-33 receptor soluble ST2 in serum could affect whether people recover from sepsis.

Sepsis is a serious illness in which the body has a massive inflammatory response to an infection. Severe sepsis and septic shock can affect multiple organs in the body including the heart, lungs, liver and brain, and is life-threatening (30–50% of people with severe sepsis or septic shock die) and requires treatment in intensive care.

Jose Alves-Filho and colleagues used experimental models of sepsis (using cecal ligation and puncture or CLP) to investigate the role of IL-33 during sepsis. The scientists induced sepsis in mice and then treated them with recombinant IL-33; IL-33-treated mice had a marked reduction in mortality compared to untreated controls and IL-33 protected mice from sepsis for 3h after CLP. The researchers found that IL-33 treatment increased the number of neutrophils migrating to the site of infection (by increasing the expression of the chemokine receptor that is crucial for neutrophil recruitment, CXCR2). This neutrophil recruitment promoted clearance of the bacterial infection and IL-33 also reduced the systemic proinflammatory cytokines (e.g. IL-6, tumour necrosis factor α and CXCL2) that occurred in response to the infective bacteria. Furthermore, the scientists analysed blood serum from healthy individuals and people who had sepsis. They found that people with sepsis had higher levels of IL-33 than healthy people, and that serum levels of soluble ST2 (the decoy receptor of IL-33) were substantially higher in people who did not survive sepsis compared to those who recovered from the disease (soluble ST2 serum levels were negligible in healthy individuals).

The research reveals a “previously unknown mechanism of action of IL-33” and further studies will show whether IL-33 could be used as a potentially novel therapy for sepsis.

ResearchBlogging.orgAlves-Filho, J., Sônego, F., Souto, F., Freitas, A., Verri, W., Auxiliadora-Martins, M., Basile-Filho, A., McKenzie, A., Xu, D., Cunha, F., & Liew, F. (2010). Interleukin-33 attenuates sepsis by enhancing neutrophil influx to the site of infection Nature Medicine DOI: 10.1038/nm.2156

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Filed under Immunology, Infectious Disease, Medicine, Uncategorized

Scientists find protein involved in OCD development

The protein Slitrk5—which is specific to neurons—is involved in the pathogenesis of obsessive–compulsive disorder (OCD) and loss of this protein leads to OCD-like behaviour in mice. The study, published in Nature Medicine, demonstrates that Slitrk5-knockout mice can be used as model of OCD and could help elucidate the molecular mechanisms that underlie this condition.

OCD is an anxiety disorder characterised by repetitive and obtrusive thoughts; this obsession leads to compulsive behaviour (e.g. handwashing or hoarding), which sufferers hopes will relieve their anxiety. Genetic analysis in humans has linked the gene SLITRK1 to Tourette’s syndrome—an OCD-like disorder—but the pathogenesis and genetics of OCD remain poorly understood.

Sergey Shmelkov and colleagues hypothesised that SLITRK5 (part of the same gene family as SLITRK1) could be involved in OCD-like behaviour and so they engineered a knockout mouse which lacked Slitrk5. The scientists observed that the Slitrk5-/- mice developed an anxiety-like behaviour and obsessively groomed, these mice had severe skin lesions and loss of facial hair that was not seen in wild-type mice. They found that fluoxetine—a selective serotonin reuptake inhibitor used in the treatment of OCD and also depression—relieved the compulsive behaviour in Slitkr5-knockout mice. The researchers then used anatomical, histological and functional analysis of the brains of Slitrk5-/- mice to further characterise their animal model of OCD. They recorded a number of observations in mice that lacked Slitkr5 compared to their wild-type counterparts: increased striatal volume, increased neural activity in the orbitofrontal cortex, abnormalities and changes to cell morphology in the striatum, decreased expression of glutamate receptors, and dysregulation of the corticostriatal circuitry.

Shmelkov et al. conclude that “Slitrk5 may have a central role in the development of OCD-like behaviour”. Some of the findings in this study are supported by existing data in humans (e.g. imaging studies imply that people with OCD have disruptions in corticostrial neurotransmission) but as yet no association with SLITRK5 has been found in humans. The investigators hope that their disease model of OCD can help investigate the pathogenesis and etiology of this prevalent anxiety disorder.

ResearchBlogging.orgShmelkov, S., Hormigo, A., Jing, D., Proenca, C., Bath, K., Milde, T., Shmelkov, E., Kushner, J., Baljevic, M., Dincheva, I., Murphy, A., Valenzuela, D., Gale, N., Yancopoulos, G., Ninan, I., Lee, F., & Rafii, S. (2010). Slitrk5 deficiency impairs corticostriatal circuitry and leads to obsessive-compulsive–like behaviors in mice Nature Medicine DOI: 10.1038/nm.2125

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