Forum for Science, Industry and Business

Sponsored by:     3M 
Search our Site:

 

Molecular 'trip switch' shuts down inflammatory response

17.12.2007
Like a circuit breaker that prevents electrical wiring from overheating and bringing down the house, a tiny family of three molecules stops the immune system from mounting an out-of-control, destructive inflammatory response against invading pathogens, researchers at the Salk Institute for Biological Studies have found.

Without these critical molecules — known as TAM receptor tyrosine kinases — patrolling immune cells on the look-out for danger would never cease activating the body’s defense system once they find an alien microbe, and the body would suffer, say the Salk investigators, whose findings appear in the Dec. 14 issue of the journal Cell.

“A truism in biology is that if you turn something on, you have to be able to turn it off, and we have found an essential switch that controls immune inflammation,” said the study’s senior investigator, Greg Lemke, Ph.D., a professor in the Molecular Neurobiology Laboratory. “The TAM signaling network represents a previously unknown, yet powerful and broadly acting, pathway for the inhibition of inflammation.”

The findings suggest that researchers might be able to manipulate the switch in ways that would be clinically beneficial, said Carla V. Rothlin, Ph.D., a postdoctoral researcher in the Lemke lab and the study’s lead author. “For example, a drug that inhibited TAMs in the short term could be given along with a therapeutic vaccine, be it one against infectious microorganisms such as anthrax or against cancer cells, in order to help the body mount a better immune response,” she said.

... more about:
»APCs »Cytokine »Switch »TAM »TLR »genes »inflammation »inflammatory »receptor

“Conversely, it may be possible to engage the TAMs early in an immune reaction in order to treat chronic autoimmune diseases such as lupus,” Rothlin said. “Knowing how important TAM receptors are to the control of inflammation in mice will aid our understanding of human immune system disorders.”

The findings are the culmination of a decade of study on TAM receptors by Dr. Lemke’s laboratory. He and his colleagues have discovered that the three TAM genes (Tyro3, Axl, Mer), also known as the Tyro3 family, produce cell surface molecules known as receptor tyrosine kinases, which regulate diverse cellular processes. When the Lemke lab produced mice that lack all three TAM receptors, the animals developed a severe autoimmune reaction, due to a malfunction in a subclass of antigen-presenting cells, or APCs, which provide the body’s first line of defense against disease-causing bacteria and viruses.

APCs constantly patrol the body’s peripheral tissues (such as the skin and lining of the gut) in search of pathogens. When they encounter foreign invaders, they unleash a “cytokine storm” — a wave of chemical messengers that jumpstart the T and B cell response. When the invaders have been successfully battled, the APCs go off duty and lymphocyte numbers and activity taper off.

Without TAM receptors, however, the APCs never shut down after their initial activation, but remain in a state of red-alert. Over time, the ensuing chronic inflammation overwhelms the regulatory mechanisms that normally distinguish “self” from “non-self”, leading to autoimmune diseases such as lupus and rheumatoid arthritis.

In his latest study, supported by the Lupus Research Institute, Lemke and his team explored how TAM receptors give the “all clear” signal to recall the emergency crews and discovered a self-limiting cycle of inflammation in dendritic cells (DCs) - APCs that play a key role in the immune response.

Patrolling DCs use toll-like receptors (TLRs) studded on their surface to “see” pathogens by recognizing their distinctive DNA patterns and configurations of cell surface proteins and sugars. Activation of TLRs leads to an initial burst of cytokines, which is then amplified in a second stage via a feed-forward loop working through cytokine receptors. In other words, TLRs turn on genes inside dendritic cells that then activate more cytokines on the cell surface.

But this same activation pathway also sows the seeds for the later inhibition of both cytokine receptor and TLR signaling. An essential stimulator of inflammation — the type 1 interferon receptor (IFNAR) — and its associated transcription factor, STAT1, turn on expression of Axl, a TAM receptor. Axl and IFNAR then physically bind together and induce the transcription of SOCS genes, whose products are potent inhibitors of both cytokine receptor and TLR signaling pathways.

This is the physical switch, the fuse that is tripped to shut down the inflammatory response, Lemke said. “It’s a cool thing. TAM receptors can’t work without binding to the interferon receptors, so that means that a pro-inflammatory signaling system is co-opted and re-directed to drive the expression of genes that will shut it down.”

“Everything we have tested that stimulates DCs engages this circuit breaker,” Rothlin says. “It’s an essential switch that keeps the immune response in balance.”

Gina Kirchweger | EurekAlert!
Further information:
http://www.salk.edu

Further reports about: APCs Cytokine Switch TAM TLR genes inflammation inflammatory receptor

More articles from Life Sciences:

nachricht Human cell-based test systems for toxicity studies: Ready-to-use Toxicity Assay (hiPSC)
05.08.2020 | Fraunhofer-Institut für Biomedizinische Technik IBMT

nachricht Molecular Forces: The Surprising Stretching Behaviour of DNA
05.08.2020 | Technische Universität Wien

All articles from Life Sciences >>>

The most recent press releases about innovation >>>

Die letzten 5 Focus-News des innovations-reports im Überblick:

Im Focus: New Strategy Against Osteoporosis

An international research team has found a new approach that may be able to reduce bone loss in osteoporosis and maintain bone health.

Osteoporosis is the most common age-related bone disease which affects hundreds of millions of individuals worldwide. It is estimated that one in three women...

Im Focus: AI & single-cell genomics

New software predicts cell fate

Traditional single-cell sequencing methods help to reveal insights about cellular differences and functions - but they do this with static snapshots only...

Im Focus: TU Graz Researchers synthesize nanoparticles tailored for special applications

“Core-shell” clusters pave the way for new efficient nanomaterials that make catalysts, magnetic and laser sensors or measuring devices for detecting electromagnetic radiation more efficient.

Whether in innovative high-tech materials, more powerful computer chips, pharmaceuticals or in the field of renewable energies, nanoparticles – smallest...

Im Focus: Tailored light inspired by nature

An international research team with Prof. Cornelia Denz from the Institute of Applied Physics at the University of Münster develop for the first time light fields using caustics that do not change during propagation. With the new method, the physicists cleverly exploit light structures that can be seen in rainbows or when light is transmitted through drinking glasses.

Modern applications as high resolution microsopy or micro- or nanoscale material processing require customized laser beams that do not change during...

Im Focus: NYUAD astrophysicist investigates the possibility of life below the surface of Mars

  • A rover expected to explore below the surface of Mars in 2022 has the potential to provide more insights
  • The findings published in Scientific Reports, Springer Nature suggests the presence of traces of water on Mars, raising the question of the possibility of a life-supporting environment

Although no life has been detected on the Martian surface, a new study from astrophysicist and research scientist at the Center for Space Science at NYU Abu...

All Focus news of the innovation-report >>>

Anzeige

Anzeige

VideoLinks
Industry & Economy
Event News

“Conference on Laser Polishing – LaP 2020”: The final touches for surfaces

23.07.2020 | Event News

Conference radar for cybersecurity

21.07.2020 | Event News

Contact Tracing Apps against COVID-19: German National Academy Leopoldina hosts international virtual panel discussion

07.07.2020 | Event News

 
Latest News

Molecular Forces: The Surprising Stretching Behaviour of DNA

05.08.2020 | Life Sciences

Carbon monoxide improves endurance performance

05.08.2020 | Health and Medicine

How tumor cells evade the immune defense

05.08.2020 | Life Sciences

VideoLinks
Science & Research
Overview of more VideoLinks >>>