Fibroblasts and immune cells: at the crossroad of organ inflammation and fibrosis.

The immune and fibrotic responses have evolved to work in tandem to respond to pathogen clearance and promote tissue repair. However, excessive immune and fibrotic responses lead to chronic inflammation and fibrosis, respectively, both of which are key pathological drivers of organ pathophysiology. Fibroblasts and immune cells are central to these responses, and evidence of these two cell types communicating through soluble mediators or adopting functions from each other through direct contact is constantly emerging.

Cerebral Malaria Is Regulated by Host-Mediated Changes in Gene Expression.

Cerebral malaria (CM), the deadliest complication of infection, is a complex and unpredictable disease. However, our understanding of the host and parasite factors that cause CM is limited. Using a mouse model of CM, experimental CM (ECM), we performed a three-way comparison between ECM-susceptible C57BL/6 mice infected with ECM-causing ANKA parasites [ANKA], ECM-resistant BALB/c mice infected with ANKA [ANKA], and C57BL/6 mice infected with NK65 that does not cause ECM [NK65].

Antigen presentation by cardiac fibroblasts promotes cardiac dysfunction.

Heart failure (HF) is a leading cause of morbidity and mortality. Studies in animal models and patients with HF revealed a prominent role for CD4+ T cell immune responses in the pathogenesis of HF and highlighted an active crosstalk between cardiac fibroblasts and IFNγ producing CD4+ T cells that results in profibrotic myofibroblast transformation. Whether cardiac fibroblasts concomitantly modulate pathogenic cardiac CD4+ T cell immune responses is unknown.

The heart under pressure: immune cells in fibrotic remodeling.

The complex syndrome of heart failure (HF) is characterized by increased left ventricular pressures. Cardiomyocytes increase in size, cardiac fibroblasts transform and make extracellular matrix, and leukocytes infiltrate the cardiac tissue and alter cardiomyocyte and cardiac fibroblast function. Here we review recent advances in our understanding of the cellular composition of the heart during homeostasis and in response to cardiac pressure overload, with an emphasis on immune cell communication with cardiac fibroblasts and its consequences in cardiac remodeling.

Increased Mitochondrial Biogenesis and Reactive Oxygen Species Production Accompany Prolonged CD4 T Cell Activation.

Activation of CD4 T cells to proliferate drives cells toward aerobic glycolysis for energy production while using mitochondria primarily for macromolecular synthesis. In addition, the mitochondria of activated T cells increase production of reactive oxygen species, providing an important second messenger for intracellular signaling pathways. To better understand the critical changes in mitochondria that accompany prolonged T cell activation, we carried out an extensive analysis of mitochondrial remodeling using a combination of conventional strategies and a novel high-resolution imaging method.

Second signals rescue B cells from activation-induced mitochondrial dysfunction and death.

B cells are activated by two temporally distinct signals, the first provided by the binding of antigen to the B cell antigen receptor (BCR), and the second provided by helper T cells. Here we found that B cells responded to antigen by rapidly increasing their metabolic activity, including both oxidative phosphorylation and glycolysis. In the absence of a second signal, B cells progressively lost mitochondrial function and glycolytic capacity, which led to apoptosis.

Toll-like receptor 9 antagonizes antibody affinity maturation.

Key events in T cell-dependent antibody responses, including affinity maturation, are dependent on the B cell's presentation of antigen to helper T cells at critical checkpoints in germinal-center formation in secondary lymphoid organs. Here we found that signaling via Toll-like receptor 9 (TLR9) blocked the ability of antigen-specific B cells to capture, process and present antigen and to activate antigen-specific helper T cells in vitro. In a mouse model in vivo and in a human clinical trial, the TLR9 agonist CpG enhanced the magnitude of the antibody response to a protein vaccine but failed to promote affinity maturation.