Out of Control Inflammation Treatment – Implications for Autism and Schizophrenia.

Key Pathway To Stop Out-Of-Control Inflammation Discovered by Georgia State Researchers


ATLANTA – A potential new strategy to developing new drugs to control inflammation without serious side effects has been found by Georgia State University researchers and international colleagues.

Jian-Dong Li, director of Georgia State’s Center for Inflammation, Immunity and Infection, and his team discovered that blocking a certain pathway involved in the biological process of inflammation will suppress it.

Inhibiting a molecule called phosphodiesterase 4B, or PDE4B, suppresses inflammation by affecting a key gene called CLYD, a gene that serves as a brake on inflammation.

The research was published in the journal Nature Communications.

Li, a professor of biology at Georgia State and a Georgia Research Alliance Eminent Scholar, explained the process of overactive inflammation using a “police” analogy.

When a pathogen – such as bacteria or viruses — infects a patient, he said, it triggers an “alarm” to which the “police” of immune system respond. In turn, it triggers neutrophil attractant called cytokines to respond, leading to inflammation that serves to help rid the body of the pathogen. But if inflammation isn’t stopped, tissue damage can result.

The pathways during the response are termed “positive,” like a gas pedal on a car, and “negative,” like a brake, with the process in the positive pathway going down the line from the pathogen to inflammation, and negative going the other direction. PDE4B is involved in controlling the negative pathway.

Many researchers have been focusing on developing anti-inflammatory agents by stopping the positive pathway, but the discovery by Li and his colleagues gives scientists a new route to stop inflammation using safer or even existing drugs proven to be non-toxic as they have found that accelerating the negative pathway will reduce inflammation.

“This is the key negative regulator that we have been searching after for years, “ Li said.

There is a need for better drugs to control inflammation, because current treatments come with serious side effects, Li said. Steroids are commonly used, but cannot be used over the long-term. Steroids suppress the immune system.

The research team included Kensei Komatsu, Ji-Yun Lee, Masanori Miyata, Jae Hyang Lim, Hirofumi Jono, Tomoaki Koga, Haidong Xu, Chen Yan, Hirofumi Kai and Jian-Dong Li.

It was supported by grants from the National Institutes of Health, grant numbers DC005843 and DC 004562. Abstracts are available at http://projectreporter.nih.gov.

The article is “Inhibition of PDE4B suppresses inflammation by increasing expression of the deubiquitinase CLYD,” in Nature Communications, available at http://hx.doi.org/10.1038/ncomms6274 or from Public Relations and Marketing Communications at 404-413-1374 or kpoeross@gsu.edu.

For more about Georgia State’s Center for Inflammation, Immunity and Infection, visit http://inflammation.gsu.edu.


Further Readings of Interest

Levels of phosphodiesterase 4A and 4B are altered by chronic treatment with psychotropic medications in rat frontal cortex.


Department of Psychiatry, Division of Neuroscience Research, University of Minnesota Medical School, MMC 392, MinneapolisAbstract

Our laboratory has recently demonstrated altered expression of phosphodiesterase (PDE) 4A and 4B in subjects with autism, bipolar disorder, and schizophrenia, suggesting disrupted cAMP signaling in these diagnostic groups.


Association between genes of Disrupted in schizophrenia 1 (DISC1) interactors and schizophrenia supports the role of the DISC1 pathway in the etiology of major mental illnesses.



Disrupted in Schizophrenia 1 (DISC1) is currently one of the most interesting candidate genes for major mental illness, having been demonstrated to associate with schizophrenia, bipolar disorder, major depression, autism, and Asperger’s syndrome. We have previously reported a DISC1 haplotype, HEP3, and an NDE1 spanning tag haplotype to associate to schizophrenia in Finnish schizophrenia families. Because both DISC1 and NDE1 display association in our study sample, we hypothesized that other genes interacting with DISC1 might also have a role in the etiology of schizophrenia.


We selected 11 additional genes encoding components of the “DISC1 pathway” and studied these in our study sample of 476 families including 1857 genotyped individuals. We performed single nucleotide polymorphism (SNP) and haplotype association analyses in two independent sets of families. For markers and haplotypes found to be consistently associated in both sets, the overall significance was tested with the combined set of families.


We identified three SNPs to be associated with schizophrenia in PDE4D (rs1120303, p = .021), PDE4B (rs7412571, p = .018), and NDEL1 (rs17806986, p = .0038). Greater significance was observed with allelic haplotypes of PDE4D (p = .00084), PDE4B (p = .0022 and p = .029), and NDEL1 (p = .0027) that increased or decreased schizophrenia susceptibility.


Our findings with other converging lines of evidence support the underlying importance of DISC1-related molecular pathways in the etiology of schizophrenia and other major mental illnesses.


Schizophrenia: A Pathogenetic Autoimmune Disease Caused by Viruses and Pathogens and Dependent on Genes


All of the pathogens implicated in schizophrenia express proteins with homology to multiple schizophrenia susceptibility gene products (Table 3). The profile of each individual pathogen is again specific for different types of gene product, but all target key members of the schizophrenia network including dopamine, serotonin and glutamate receptors as well as neuregulin and growth-related or DISC1 related pathways. This is the case even when no filter is used. Interestingly, both the rubella and the influenza viruses target members of the translation initiation complex, which has been implicated in myelination and oligodendrocyte survival [4, 40]. Oligodendrocyte cell loss and myelination defects are prominent in the schizophrenic brain”

Schizophrenia susceptibility genes directly implicated in the life cycles of pathogens: Cytomegalovirus, influenza, herpes simplex, rubella, and Toxoplasma gondii


“Certain genes associated with schizophrenia, including those also concerned with neurophysiology, are intimately related to the life cycles of the pathogens implicated in the disease. Several genes may affect pathogen virulence, while the pathogens in turn may affect genes and processes relevant to the neurophysiology of schizophrenia. For such genes, the strength of association in genetic studies is likely to be conditioned by the presence of the pathogen, which varies in different populations at different times, a factor that may explain the heterogeneity that plagues such studies. This scenario also suggests that drugs or vaccines designed to eliminate the pathogens that so clearly interact with schizophrenia susceptibility genes could have a dramatic effect on the incidence of the disease.”


DISC1 – http://en.wikipedia.org/wiki/DISC1

Mice with lowered levels of DISC1 expression exhibit abnormal response to electrical stimulation, a decrease of dopamine synthesis, and an inability to filter unnecessary sensory information. Studies of expression of mutant DISC1 prenatally and postnatally have demonstrated varying effects, indicating the possibility that early postnatal expression of mutant DISC1 causes features of autism. Many more studies are necessary to confirm these suggestions.[25]

This entry was posted in Autism, co-morbid, Immune System, Inflammation, Mice, Schizophrenia, Treatment. Bookmark the permalink.

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