Ciske, E. | Search bioRxiv

bioRxiv2024

Macrophage-derived CCL24 promotes fibrosis and worsens cardiac dysfunction during heart failure

Inflammation is a significant risk factor and contributes to cardiovascular disease by driving both adaptive and maladaptive processes. Macrophages are the most abundant immune cells in the heart and play an important role in the remodeling of cardiac tissue. We have previously shown an overall protective function of resident cardiac macrophages after pressure-overloaded injury. However, a subpopulation of resident macrophages also expresses high levels of the profibrotic CC motif chemokine ligand 24 (CCL24), suggesting a dichotomous role in pressure overload-induced cardiac remodeling. Here, we report that following transverse aortic constriction CCL24 knockout (CCL24 KO) mice have improved systolic function, cardiac wall enlargement, as well as increased myocyte surface area and hypertrophy, suggesting that CCL24 disrupts compensatory hypertrophy. TAC-operated CCL24 KO mice also displayed reduced fibrosis and diminished expression of fibrotic genes, implying a pro-fibrotic role for CCL24. Indeed, CCL24 induced the proliferation and activation of primary mouse fibroblasts in a process that required CCR3, the sole G protein-coupled receptor for CCL24. Correspondingly, selective ablation of CCR3 in fibroblasts improved cardiac function and ameliorated fibrosis following pressure overload. Administration of a CCL24 blocking antibody or a CCR3 antagonist both improved cardiac function in pressure-overloaded mice, highlighting the CCL24-CCR3 axis as a potential therapeutic target for heart failure. Finally, CCL24 deficiency improved cardiac function and ameliorated fibrosis during physiological aging. Overall, these results show that macrophage-derived CCL24 aggravates fibrosis via the CCR3 receptor, leading to impaired cardiac function in acute and chronic heart failure.

immunology↗

bioRxiv2023

Pyruvate Oxidation Sustains B Cell Antigen-Specific Activation to Exacerbate MASH

B cells play a crucial role in the pathogenesis of metabolic dysfunction-associated steatohepatitis (MASH), a severe form of steatotic liver disease that if persistent can lead to cirrhosis, liver failure, and cancer. Chronic inflammation and fibrosis are key features of MASH that determine disease progression and outcomes. Recent advances have revealed that pathogenic B cell-derived cytokines and antibodies promote the development of MASH. However, the mechanisms through which B cells promote fibrosis and the metabolic adaptations underlying their pathogenic responses remain unclear. Here, we report that a subset of mature B cells with heightened cytokine responses accumulate in the liver and promote inflammation in MASH. To meet the increased energetic demand of effector responses, B cells increase their ATP production via oxidative phosphorylation (OXPHOS) fueled by pyruvate oxidation in a B cell receptor (BCR)-specific manner. Blocking pyruvate oxidation completely abrogated the inflammatory capacity of MASH B cells. Accordingly, the restriction of the BCR led to MASH attenuation, including reductions in steatosis, hepatic inflammation, and fibrosis. Mechanistically, BCR restriction decreased B cell maturation, activation, and effector responses in the liver, accompanied by decreased T cell- and macrophage-mediated inflammation. Notably, attenuated liver fibrosis in BCR-restricted mice was associated with lower IgG production and decreased expression of Fc-gamma receptors on hepatic stellate cells. Together, these findings indicate a key role for B cell antigen-specific responses in promoting steatosis, inflammation, and fibrosis during MASH.

physiology↗