Bacteria-Sensing Immune Cells On Skin May Yield Potential Treatment Targets For Allergic Reactions

Researchers have identified the mechanism by which cutaneous group 2 innate lymphoid (ILC2) cells sense and respond to bacteria and skin allergens, paving the way to potential new treatment targets.

"Innate lymphoid cells are being increasingly recognized to play key roles in disease, but we are still learning about ways in which they are activated and how they respond," Dr. Graham Ogg of the University of Oxford.

"So far, most studies have focused on innate lymphoid cell stimulation by soluble mediators such as cytokines, inflammatory lipids and through cell-to-cell contact," he said. "So, we were surprised that human ILC2 cells can respond directly to bacterial products and that this may lead to production of different cytokines, including IL-6."

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"We found that the findings could be explained by the innate lymphoid cell expression of the sensing molecules TLR2 and NOD2," he explained. "Furthermore, patients with some forms of inflammatory bowel disease have mutations in the gene encoding NOD2, which can influence cytokine production by ILC2 cells."

As reported in Science Immunology, and building on previous work, Dr. Ogg and colleagues analyzed how ILC2s in the skin, which are positioned and programmed to respond to invading pathogens, are activated in response to a barrier compromise or other immunological threat.

To investigate the cells' potential for direct sensing of skin pathogens and allergens, the team induced blisters in study participants by exposing them to house dust mite allergens. After sorting out ILC2s from blister fluid extracts, they performed RNA sequencing and found, as Dr. Ogg noted, that ILC2s express nucleotide-binding oligomerization domain-containing protein 2 (NOD2) and TLR2, bacteria-sensing pattern recognition receptors (PRRs) that are expressed by numerous cell types.

In vitro analyses showed that both blood-circulating and skin-residing ILC2s express NOD2 and TLR2 and can sense an array of bacteria, including Staphylococcus aureus, Staphylococcus epidermidis, and Pseudomonas aeruginosa, and that PRRs induce ILC2 production of inflammatory molecules such as IL-6 to help regulate skin microflora.

Additional in vitro experiments confirmed that NOD2 stimulated both the IL-6 profile and autophagy in ILC2s after exposure to bacteria. However, as Dr. Ogg also noted, these processes were impaired in patients with NOD2 mutations.

Summing up, the authors state, "Here, we have identified a role for ILC2 NOD2 signaling in the differential regulation of ILC2-derived IL-6 and have reported a previously unrecognized pathway of direct ILC2 bacterial sensing."

Dr. Adam Friedman, Professor and Chair of Dermatology at George Washington University in Washington DC, commented on the study in an email to Reuters Health, "The success of personalized medicine rests on a strong foundation and understanding of the underpinnings of physiology and disease."

"The investigators identify a novel mechanism by which local immune cells maintain the balance of the skin barrier (which includes the living part of that barrier, the skin microbiota), and highlight how dysregulation of said system could lead to skin disease," he said. "Such an understanding can ultimately lead to new, targeted therapeutic approaches."

—Marilynn Larkin

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