R01AI189915

Prenatal programming of immune cells for tissue repair and remodeling in asthma - Project summary/abstract

Airway remodeling is a key feature of asthma.

Mechanisms of airway remodeling are not fully understood.

Remodeling and inflammation may occur independently, suggesting mechanistic divergence of these two features in some endotypes of asthma.

Airway remodeling has been detected in children as young as 1-year-old, pointing to a possibility of an inborn defect.

Inborn defects are either genetic or a result of parental environmental exposures.

For asthma, there are studies suggesting both mechanisms.

Using a mouse model, we discovered an inborn predisposition to airway remodeling and asthma that was caused by maternal exposure to diesel exhaust particles (DEP).

Susceptibility to airway remodeling was linked to impaired embryonic growth and emergence of a reparative mast cell (MC) subset.

Embryos and pups of DEP exposed mothers had reduced body weight.

Inborn impairment of growth was linked to abnormal activation of lung mesenchymal cells.

Compared to lungs of PBS neonates, the lung interstitium of DEP neonates was more strongly positive for ACTA2, a marker of wound-healing myofibroblasts, and airway smooth muscle was thickened.

Mesenchymal cell activation was linked to numerical expansion of lung MCs.

Postnatal exposure to an allergen greatly exacerbated stromal pathology, leading to exuberant remodeling of the airways.

DEP-elicited airway remodeling was MC dependent; MC deficiency reduced remodeling, and unexpectedly, enhanced T2 inflammation in the lung.

In sum, our results suggested that under conditions of harmful maternal exposure, in an effort to rescue embryonic growth, MC responses shifted from pro-inflammatory/pro-allergic to anti-inflammatory and tissue-reparative.

Our scRNA-seq experiment followed by flow cytometry and adoptive transfer experiments indicated that these new functions were attributable to a novel MC subset that expanded greatly in offspring of DEP-exposed mothers, produced an array of tissue-reparative and anti-inflammatory factors, and after being adoptively transferred into lungs of MC KO recipients, restored pulmonary expression of repair/remodeling markers ACTA2 and VIM.

To capture the postulated “rescue” function of this subset, we have named it “Orpheus MCs” after the Greek hero who attempted to rescue his wife from the underworld.

We then found that allergic wheezing preschoolers had increased percentage of Orpheus MC progenitors in the blood, underscoring the human relevance of our project.

Mechanistic studies on Orpheus MC-specific receptors and their ligands suggested roles of two ligands in developmental programming of Orpheus MCs.

Together, our hypothesis is that environmentally-induced inborn predisposition to asthmatic airway remodeling is in part due to emergence of the tissue-reparative anti-inflammatory Orpheus MC subset.

In Aim 1, using our mouse model, we will elucidate roles of Orpheus MCs in asthma.

In Aim 2, we will study importance of two identified ligands in programming Orpheus MC responses in asthma.

In Aim 3, we will study relevance of the Orpheus MC lineage for human asthma.

National Jewish Health

<P>THE GOALS ARE:</P><UL><LI>TO FOSTER FUNDAMENTAL CREATIVE DISCOVERIES, INNOVATIVE RESEARCH STRATEGIES, AND THEIR APPLICATIONS AS A BASIS FOR ULTIMATELY PROTECTING AND IMPROVING HEALTH;</LI><LI>TO DEVELOP, MAINTAIN, AND RENEW SCIENTIFIC HUMAN AND PHYSICAL RESOURCES THAT WILL ENSURE THE NATION'S CAPABILITY TO PREVENT DISEASE;</LI><LI>TO EXPAND THE KNOWLEDGE BASE IN MEDICAL AND ASSOCIATED SCIENCES IN ORDER TO ENHANCE THE NATION'S ECONOMIC WELL-BEING AND ENSURE A CONTINUED HIGH RETURN ON THE PUBLIC INVESTMENT IN RESEARCH; AND</LI><LI>TO EXEMPLIFY AND PROMOTE THE HIGHEST LEVEL OF SCIENTIFIC INTEGRITY, PUBLIC ACCOUNTABILITY, AND SOCIAL RESPONSIBILITY IN THE CONDUCT OF SCIENCE.</LI></UL><P>IN REALIZING THESE GOALS, THE NIH PROVIDES LEADERSHIP AND DIRECTION TO PROGRAMS DESIGNED TO IMPROVE THE HEALTH OF THE NATION BY CONDUCTING AND SUPPORTING RESEARCH:</P><UL><LI>IN THE CAUSES, DIAGNOSIS, PREVENTION, AND CURE OF HUMAN DISEASES;</LI><LI>IN THE PROCESSES OF HUMAN GROWTH AND DEVELOPMENT;</LI><LI>IN THE BIOLOGICAL EFFECTS OF ENVIRONMENTAL CONTAMINANTS;</LI><LI>IN THE UNDERSTANDING OF MENTAL, ADDICTIVE AND PHYSICAL DISORDERS; AND</LI><LI>IN DIRECTING PROGRAMS FOR THE COLLECTION, DISSEMINATION, AND EXCHANGE OF INFORMATION IN MEDICINE AND HEALTH, INCLUDING THE DEVELOPMENT AND SUPPORT OF MEDICAL LIBRARIES AND THE TRAINING OF MEDICAL LIBRARIANS AND OTHER HEALTH INFORMATION SPECIALISTS.</LI></UL>

93.855 - Allergy and Infectious Diseases Research

National Institute of Allergy and Infectious Diseases (NIAID) [HHS - NIH]

Denver, Colorado 802062761 United States

Single Zip Code

NIH Research Project Grant (Parent R01 Clinical Trial Not Allowed) (PA-25-301)