Current research suggests that stress may activate immune cells in your skin, resulting in inflammatory skin disease. The related report by Joachim et al., “Stress-induced Neurogenic Inflammation in Murine Skin Skews Dendritic Cells towards Maturation and Migration: Key role of ICAM-1/LFA-1 interactions,” appears in the November issue of The American Journal of Pathology.Skin provides the first level of defense to infection, serving not only as a physical barrier, but also as a site for white blood cells to attack invading bacteria and viruses. The immune cells in skin can over-react, however, resulting in inflammatory skin diseases such as atopic dermatitis and psoriasis.

Stress can trigger an outbreak in patients suffering from inflammatory skin conditions. This cross talk between stress perception, which involves the brain, and the skin is mediated the through the “brain-skin connection”. Yet, little is know about the means by which stress aggravates skin diseases.

Researchers lead by Dr. Petra Arck of Charité, University of Medicine Berlin and McMaster University in Canada, hypothesized that stress could exacerbate skin disease by increasing the number of immune cells in the skin. To test this hypothesis, they exposed mice to sound stress. Dr. Arck’s group found that this stress challenge resulted in higher numbers of mature white blood cells in the skin. Furthermore, blocking the function of two proteins that attract immune cells to the skin, LFA-1 and ICAM-1, prevented the stress-induced increase in white blood cells in the skin.

Taken together, these data suggest that stress activates immune cells, which in turn are central in initiating and perpetuating skin diseases. Fostered by the present observation, the goal of future studies in Dr. Arck’s group is to prevent stress-triggered outbreaks of skin diseases by recognizing individuals at risk and identifying immune cells suitable to be targeted in therapeutic interventions.

Amoebas glide toward their prey with the help of a protein switch that controls a molecular compass, biologists at the University of California, San Diego have discovered.

Their finding, detailed in this week’s issue of the journal Current Biology, is important because the same molecular switch is shared by humans and other vertebrates to help immune cells locate the sites of infections.

The amoeba Dictyostelium finds bacteria by scent and moves toward its meal by assembling a molecular motor on its leading edge. The active form of a protein called Ras sets off a cascade of signals to start up that motor, but what controlled Ras was unknown.

Richard Firtel, professor of biology along with graduate student Sheng Zhang and postdoctoral fellow Pascale Charest tested seven suspect proteins by disrupting their genes. One called NF1, which matches a human protein, proved critical to chemical navigation.

NF1 turns Ras off. Without this switch mutant amoebas extended false feet called pseudopodia in all directions and wandered aimlessly as Ras flickered on and off at random points on their surfaces. “You have to orient Ras in order to drive your cell in the right direction,” Firtel said.

In contrast, normal amoebas with working versions of NF1 elongate in a single direction and head straight for the most intense concentration of bacterial chemicals, the team reports.

The biochemical components of the system match those found in vertebrate immune cells called neutrophils that hunt down bacterial invaders, suggesting that the switch might be a key navigational control for many types of cells, Firtel said. “The pathway and responses are very similar and so are the molecules.”

By killing off “angry” immune cells that take up residence in obese fat and muscle tissue, researchers have shown that they can rapidly reverse insulin resistance in obese mice.  The findings reported in the October Cell Metabolism, a publication of Cell Press, suggest that treatments aimed at specific subsets of the so-called macrophage cells might offer a very effective new antidiabetic therapy, according to the researchers.

” We used a genetic ‘trick’ that allowed us to rapidly kill these macrophages,” said Jerrold Olefsky of the University of California, San Diego.  “The treatment killed these cells within hours, and insulin resistance simply reversed itself.  It argues strongly that macrophages are causative for the inflammation that leads to diabetes [in those who are obese].”

” The most interesting thing is that this reversal occurs very rapidly,” added Jaap Neels of INSERM in France, who led the work while in Olefsky’s lab.  “Twenty-four hours later the animals’ insulin response had completely normalized.  They were still obese, but no longer insulin resistant.”

Of course, Neels said, the strategy used in the obese mice wouldn’t translate to the clinic directly.  It’s also unclear whether or not it is the same subtype of macrophage cells that invade fat tissue in people who are obese.  Nevertheless, the findings suggest that you would not necessarily need to target all macrophages to have a beneficial effect on the diseases associated with obesity.  That’s critical because “you don’t want to knock out the whole immune system.”

Over the past decade, it has become quite clear that obesity gives rise to a state of chronic, low-grade inflammation that contributes to insulin resistance and type 2 diabetes, the researchers explained.

Olefsky and Neels’ team along with others recently found that a specific subset of macrophages invades obese fat and muscle tissue.  Although little was known about them, those macrophages are defined by a CD11c marker expressed on their surfaces.  They also produce high levels of proinflammatory chemicals that are linked to the development of obesity-associated insulin resistance.

In the new study, the researchers tested the idea that killing those cells would reverse the inflammatory symptoms that come with obesity using a mouse model developed earlier in which the CD11c-expressing macrophages were artificially made susceptible to diphtheria toxin.

They found that treatment with the toxin not only reversed the animals’ resistance to insulin, but also led to a marked decline in inflammatory signs through the body.  The treated animals showed a decline in the CD11c macrophages in both fat and muscle, they confirmed.

” It shows that high triglycerides in muscle don’t necessarily have to lead to insulin resistance as it has been thought—as long as the high lipid levels aren’t accompanied by inflammation,” Neels said.

The obese mice also had less fat in their livers, an important find given the epidemic of obesity-associated fatty liver disease.

If a unique marker can be identified on the macrophages found in human fat tissue, a drug could be designed to take advantage of those features to bind and kill them, Neels said.  Alternatively, it may be possible to convert the macrophage cells into another, less inflammatory type.

Scientists report online this week in Nature that they have linked the health of specialized gut immune cells to a gene associated with Crohn’s disease, an often debilitating and increasingly prevalent inflammatory bowel disorder.

The link to immune cells intrigued researchers at Washington University School of Medicine in St. Louis because they and others believe Crohn’s disease is caused by misdirected immune responses in the intestine that damage gut tissue.  In addition, cells in the mouse model scientists used for the study had altered genetic activity that could lead to increased production of certain hormones.  Those same hormones are elevated in some Crohn’s patients.

“We now have a significant new piece of the puzzle that is Crohn’s disease, but not the solution just yet,” says senior author Herbert W. “Skip” Virgin, M.D., Ph.D., the Edward Mallinckrodt Professor and head of the Department of Pathology and Immunology.  “As many as 30 different areas in human DNA have potential links to Crohn’s disease, and to develop new treatments it’s going to be essential to find out how each of them, as well as environmental factors, contribute to the disorder.”

Crohn’s disease is one of the most common inherited bowel disorders.  In 2002, epidemiologists estimated that it affected 400,000 to 600,000 patients in North America.  Symptoms include diarrhea, abdominal pain, vomiting and weight loss.  The condition can lead to partial or full intestinal blockages, which can require surgical treatment.

Research previously revealed that some Crohn’s disease patients have a mutation in a gene known as Atg16L1.  The mutation increases risk but doesn’t automatically lead to Crohn’s disease.  To learn more, Ken Cadwell, Ph.D., a postdoctoral student in Virgin’s lab, created and studied two lines of mice with a genetic alteration that reduced their ability to make the Atg16L1 protein.

Cadwell and his colleagues found decreased Atg16L1 protein had pronounced effects on Paneth cells, which are immune cells in the lining of a portion of the small intestine.  These cells make proteins and antimicrobial peptides that they package as granules and secrete into the intestine to defend the body against infection.

“When they have less Atg16L1, the Paneth cells survive, but their ability to secrete granules is significantly impaired,” Cadwell says.

Virgin consulted with co-authors Ellen Li, M.D., Ph.D., and Thaddeus Stappenbeck, M.D., Ph.D., Washington University researchers who study and treat Crohn’s disease patients at Barnes-Jewish Hospital.  When surgery becomes necessary to repair a patient’s bowel, Li collects samples removed from the intestine for research.  Selecting tissue from patients with mutated Atg16L1, researchers compared human Paneth cells to cells from their mouse model and found what Virgin calls “striking similarities.”

To learn how Atg16L1 helps the Paneth cell, scientists conducted a follow-up experiment where a related gene, Atg5, was knocked out in mice.  Like Atg16L1, Atg5 contributes to an important process called autophagy that lets cells consume and reuse their own resources and may have other functions as well.  Paneth cells in this line of mice had impairments similar to the first line, suggesting that Atg16L1’s contributions to the Paneth cell may be linked to autophagy.

“We don’t yet know why having abnormal Paneth cells would predispose a person to Crohn’s disease or to what degree other genes linked to Crohn’s may affect the Paneth cell, but those are just a few of the very interesting questions to follow up on from these results,” Virgin says.

Oliver Söhnlein and colleagues, at the Karolinska Institutet, Sweden, have identified a new function for a number of proteins secreted by human immune cells known as neutrophils or PMNs: they enhance the uptake of bacteria by other immune cells (known as macrophages) that are capable of destroying the microbes.

In the study, proteins secreted by human PMNs, specifically HBP and HNP1-3, were found to enhance the in vitro ability of human and mouse macrophages to take up bacteria coated in the immune molecule IgG. Mechanistically, HBP and HNP1-3 activated the macrophages to secrete soluble factors that, in turn, induced the macrophages to express proteins to which IgG can bind (CD32 and CD64). The authors therefore suggest that HBP and HNP1–3 secreted by PMNs have a role in clearing bacterial infections.