[F31] Investigating neuro-immune interactions in pulmonary homeostasis and disease
Ente: National Heart Lung and Blood Institute
Scadenza: 2029-06-30
Importo max: 46.186 EUR
Paese: US
Descrizione
PROJECT SUMMARY
The lung is a critical barrier tissue, continually exposed to the external environment and respiratory insults.
Inflammation is the appropriate response to respiratory insults; however sustained or prolonged inflammation
can exacerbate the injury itself. One, largely fatal, outcome of sustained inflammation is interstitial lung disease
(ILD)—a group of pathologies characterized by inflammation, lung damage, and often fibrosis. The causative
factors of ILD are typically unknown, or idiopathic, though there is a growing body of evidence detailing ILD
etiology linked to select pharmaceutical exposure. Clinical reports show that modulation of neuropeptide
Calcitonin Gene Related Peptide (CGRP), or disruption of immune tolerance can promote ILD. Dendritic cells
(DCs) represent the bridge between these observations, as my preliminary data show that human and murine
DCs express the CGRP receptor and closely associate with CGRP+ sensory axons (nociceptors) surrounding
the airway. DCs are known to accumulate in fibrotic ILD, a pathology conserved in preclinical models. I observed
that pulmonary nociceptors display extensive neuroplasticity in a pre-clinical model of ILD, where they branch
toward DC-enriched fibrotic lesions and release CGRP. DCs act at the interface of immunity where they have
two major divisions: (i) immunogenic DCs promote the immune response through T-cell activation and (ii)
tolerogenic DCs initiate peripheral tolerance through regulatory T-cells. Intriguingly, following nocicpetor
branching and CGRP release, clusters of Pd-l1+ tolerogenic DCs and regulatory T-cells are observed. Integration
of these data with transcriptional analyses supports the hypothesis that neuro-immune interactions activate and
rewire DCs toward the tolerogenic fate via CGRP signaling. Using pharmacologic approaches to modulate CGRP
signaling, this proposal will investigate the structure of nociceptor-DC interactions and define the transcriptional
and functional impact of CGRP signaling on pulmonary DC biology. With support from my sponsors, committees,
and collaborators—this project will provide training in pulmonary neuroimmunology as well as new technical and
analytic skills. Technology and expertise to support this training are in place. This research is also supported by
the literature where anti-inflammatory effects of CGRP signaling have been demonstrated. Further
understanding the signals that regulate tolerogenic DCs are of significant clinical interest; tolerogenic DC therapy
can be used to manage autoimmune disease and other inflammatory conditions, and may also represent a
unique clinical strategy for the management of ILD.
Istituzione: GEORGE WASHINGTON UNIVERSITY
PI: Jaclyn Andricovich
Progetto: 1F31HL182268-01A1
Settori: National Heart Lung and Blood Institute
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