Overview:

Researchers from the NIH and Weill Cornell Medicine have identified a molecule in lymphocytes that could potentially lead to treatments for inflammatory disorders, such as atopic dermatitis, food allergies and asthma. The same molecule, when blocked, provides insights on treatment for parasitic worms that infect more than a billion people living in tropical and sub-tropical regions.

The molecule, a neuropeptide called calcitonin gene-related peptide (CGRP), was originally identified as a product of neurons and nerve endings. CGRP is also produced in the lymphocytes in the lungs and gut of mammals. Lymphocytes carry sensors to respond to CGRP. The findings appeared July 25, 2019 in the journal Immunity. There are currently drugs on the market that block CGRP from neurons for treatment of migraine headaches and this study suggests that CGRP blockage could impact immune-mediated disease as well. This study also suggests that future drugs that enhance CGRP signaling may have potential to treat allergic diseases.

Select Highlights:

• Researchers studied mice infected with helminth worms, which are transmitted through human waste and can contaminate soil. This family of worms, which includes roundworms, whipworms and hookworms, can cause intestinal blood loss and can also cause diarrhea and dysentery.  These parasites induce “type 2” immune responses in hosts, which can also be seen in asthma and allergies.
• Single cell sequencing was used to examine white blood cells taken from mice in the study. While many studies examine how groups of cells in tissues or organs act, this technology allows scientists to focus on the variability in gene expression among the cells.
• The scientists found a subset of lymphocytes in the lung and gut that produces and responds to CGRP, which diminishes some aspects of the body’s type 2 immune response. When the researchers studied mice that could not produce or respond to CGRP, they found that these altered mice were able to fight off the worm infection more quickly than normal mice. This is due to a more robust immune response in the absence of CGRP.
• This work reveals a new aspect of regulation of type 2 immune responses, which may impact how scientists think about allergies and asthma, as well as parasitic infection.

Perspectives:

“We were surprised to unearth a role for a molecule linked to migraines in regulating immune response. But that is the beauty of using single cell sequencing, you sometimes see the unexpected.”

John O’Shea, M.D., study author, Scientific Director and Chief, Molecular Immunology and Inflammation Branch, National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)

“This collaborative, multi-center study helped us identify a new function for CGRP, essentially acting like an off-switch for allergic inflammation in mouse models.”

David Artis, Ph.D., study co-author, Director of the Jill Roberts Institute for Research in Inflammatory Bowel Disease, Director of the Friedman Center for Nutrition and Inflammation and the Michael Kors Professor of Immunology at Weill Cornell Medicine. Dr. Artis has contributed to scientific advisory boards for MedImmune, Pfizer, the Kenneth Rainin Foundation, and Food Allergy Research & Education.

NIH researchers from NIAMS and the National Institute of Allergy and Infectious Diseases (NIAID) contributed to this study.

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Neuropeptide CGRP Limits Group 2 Innate Lymphoid Cell Responses and Constrains Type 2 Inflammation.  Nagashima H, Mahlakõiv T, Shih HY, Davis FP, Meylan F, Huang Y, Harrison OJ, Yao C, Mikami Y, Urban Jr. JF, Caron KM, Belkaid Y, Kanno Y, Artis D & O’Shea JJ. Immunity, 2019 July 16 pii: S1074-7613(19)30279-1. DOI: https://doi.org/10.1016/j.immuni.2019.06.009