loading
loading
NIH grant 1R21AI196947-01A1: Formyl peptide receptor-mediated inflammation and pulmonary fibrosis
Institute: {'code': 'AI', 'abbreviation': 'NIAID', 'name': 'National Institute of Allergy and Infectious Diseases', 'admin_org_id': '12500003', 'admin_funding_url': ''}. PI: Jan Christian Lood. Award: $264750.
Start: 2026-09-11T00:00:00.
Summary: Neutrophils participate in our immune defense through several mechanisms upon recognizing
danger. One main neutrophil pattern recognition receptor, formyl peptide receptor 1 (FPR1), recognizes N-
formyl methionine peptides derived from bacteria or damaged tissue. FPR1 engagement is one of the early
signals required for recruitment of neutrophils to target tissue, and subsequent activation and inflammation.
Although beneficial from a host-pathogen perspective, exaggerated neutrophil activation has been linked to
inflammation and autoimmunity, including rheumatoid arthritis (RA). Though primarily a disease of the joints,
extra-articular manifestations are common, with interstitial lung disease (ILD) occurring in up to 10% of the
patients with RA. RA-ILD is a leading cause of death in patients with RA, with progression occurring even on
current treatment strategies. Thus, there is a clear need to improve outcomes in patients with RA-ILD. The aim
of the present study is to explore the role of FPR1 in the RA-ILD pathogenesis, with a focus on neutrophil
activation. The premise is that N-formyl methionine peptides will engage FPR1 on neutrophils resulting in local
inflammation and organ damage. To investigate this, we have two main aims. The first aim will characterize the
N-formyl methionine peptides in RA-ILD using liquid chromatography tandem mass spectrometry of
immunoprecipitated peptides from plasma and sputum of patients with RA (n=100), RA-ILD (n=50) and healthy
controls (n=50). Peptides, either immunoprecipitated, or synthesized, will be validated for functional capacity
using FPR1 cell reporter assays as well as in-house neutrophil activation assays in presence of FPR1
antagonist, Cyclosporin H. The second aim investigated the role of FPR1 in neutrophil-driven inflammation in
vivo using the collagen-induced arthritis (CIA) mouse model. In the first subaim, arthritis and lung fibrosis will
be examined in mice with genetic deficiency of FPR1 (n=10 mice/group). In the second subaim, FPR1
antagonist, Boc-2, will be delivered either preventative (day 1) or therapeutic (day 35) to determine the ability
to intervene with FPR1-driven inflammation in development of joint and lung damage. At the completion of the
proposed research, our expected outcomes are to have identified novel mechanisms regulating neutrophil-
mediated inflammation, and in particular the important role of FPR1 in RA-ILD pathogenesis. We expect this
work to have a positive impact because it will offer novel biomarkers to assess disease activity and organ
damage, potentially allowing for early preventive measures, as well as identify targetable pathway to limit
neutrophil-mediated inflammation and organ damage in RA-ILD. Finally, we anticipate our findings to have
broad applicability also to other conditions wherein exaggerated neutrophil activation is seen, including lupus
and other inflammatory lung diseases.document fetched 2026-09-20 02:42