Garcia, R. A. | Search bioRxiv

bioRxiv2025

Formyl-peptide receptor type 2 activation mitigates secondary organ damage in inflammatory arthritis

Rheumatoid arthritis (RA) is associated with heart and lung dysfunction. Current therapies fail to attenuate such complications. Here, we identify formyl-peptide receptor type 2 (FPR2) as therapeutic target to treat heart and lung dysfunction associated with inflammatory arthritis. Arthritic mice on high levels of dietary homocysteine develop cardiac diastolic dysfunction and reduced lung compliance, mirroring two comorbidities in RA. Therapeutic administration of a small molecule FPR2 agonist (BMS986235) to hyper-homocysteine arthritic mice prevented diastolic dysfunction (monitored by echocardiography) and restored lung compliance. These tissue-specific effects were secondary to reduced neutrophil infiltration, modulation of fibroblast activation and phenotype (in the heart) and attenuation of monocyte and macrophage numbers (in the lung). A dual FPR1/2 agonist (compound 43) failed to prevent the reduction in lung compliance of arthritic mice and promoted accumulation of inflammatory monocytes and pro-fibrotic macrophages in lung parenchyma. This cellular response lies downstream of FPR1-mediated potentiation of CCL2-dependent monocyte chemotaxis and activation. This finding supports therapeutic development of selective FPR2 agonists to mitigate two impactful comorbidities associated with inflammatory arthritides.

pharmacology and toxicology↗

bioRxiv2021

Climate and genetic diversity change in mammals during the Late Quaternary

Conservation decisions and future scenarios are in need of past baselines on climate change impacts in biodiversity. Although we know that climate change has contributed to diversity shifts in some mammals1,2,3,4,5,6,7, previous research often assumed that climate change is invariable across species ranges. We are therefore still ignorant of the true rates of climate change experienced by species assemblages over the last millennia, their impacts on intraspecific diversity, and how they compare to future climate change projections. Here, we use more than 9,000 Late Quaternary records, including fossils and ancient and modern DNA sequences, millennial-scale paleoclimatic reconstructions over the last 50,000 years and future climate change projections to document rates of climate change velocity and dynamics in genetic diversity experienced by an assemblage of 16 extinct and extant Holarctic mammal species. Extinct megafauna experienced velocities more than 15 times faster than the extant species, up to 15.2 km per decade. Notably, extant large-bodied grazers lost almost a 65% of their pool of genetic diversity since the Late Pleistocene, which indicates reduced ability to adapt to on-going global change. Additionally, mammal species experienced overall climate change velocities slower than that projected for the end of the 21st century but punctuated by comparable fast climate change episodes. Our results provide baselines on the impacts of ongoing and future climate change on the diversity of mammal species.

ecology↗