Midkine drives cardiac inflammation by promoting neutrophil trafficking and NETosis in myocarditis

Heart failure due to dilated cardiomyopathy is frequently caused by myocarditis. However, the pathogenesis of myocarditis remains incompletely understood. Here, we report the presence of neutrophil extracellular traps (NETs) in cardiac tissue of patients and mice with myocarditis. Inhibition of NET formation in experimental autoimmune myocarditis (EAM) of mice substantially reduces inflammation in the acute phase of the disease. Targeting the cytokine midkine (MK), which mediates NET formation in vitro, not only attenuates NET formation in vivo and the infiltration of polymorphonuclear neutrophils (PMNs) but also reduces fibrosis and preserves systolic function during EAM. Low-density lipoprotein receptor-related protein 1 (LRP1) acts as the functionally relevant receptor for MK-induced PMN recruitment as well as NET formation. In summary, NETosis substantially contributes to the pathogenesis of myocarditis and drives cardiac inflammation, probably via MK, which promotes PMN trafficking and NETosis. Thus, MK as well as NETs may represent novel therapeutic targets for the treatment of cardiac inflammation

Expression of Membrane-Bound CC Chemokine Ligand 20 on Follicular T Helper Cells in T–B-Cell Conjugates

The CC chemokine receptor 6 (CCR6) and its sole chemokine ligand CC chemokine ligand 20 (CCL20) display an emerging role in the coordination of humoral immune responses. Recent studies demonstrate a role of this chemokine axis in the migration of B cells to key immunological sites during an immune response, and facilitating the generation of high-quality antibodies. Very little, however, is known about CCL20 and its role in these functions. We undertook a preliminary investigation into the expression and function of CCL20 and demonstrate its well-noted upregulation in the spleen during immunization. Furthermore, we show that most follicular T helper (Tfh) cells can be CCR6+ and can produce CCL20. Surprisingly, CCL20 cannot only be found in the cytoplasm but also on the surface of these cells and their precursors. Analysis of T–B-cell conjugates revealed that mature Tfh cells, but not their precursors, are highly enriched in the conjugates. Further functional studies are needed to unravel the precise role of CCL20 in coordinating T and B cell interactions during the humoral immune response

Differences in Cell-Intrinsic Inflammatory Programs of Yolk Sac and Bone Marrow Macrophages

Background: Tissue-resident macrophages have mixed developmental origins. They derive in variable extent from yolk sac (YS) hematopoiesis during embryonic development. Bone marrow (BM) hematopoietic progenitors give rise to tissue macrophages in postnatal life, and their contribution increases upon organ injury. Since the phenotype and functions of macrophages are modulated by the tissue of residence, the impact of their origin and developmental paths has remained incompletely understood. Methods: In order to decipher cell-intrinsic macrophage programs, we immortalized hematopoietic progenitors from YS and BM using conditional HoxB8, and carried out an in-depth functional and molecular analysis of differentiated macrophages. Results: While YS and BM macrophages demonstrate close similarities in terms of cellular growth, differentiation, cell death susceptibility and phagocytic properties, they display differences in cell metabolism, expression of inflammatory markers and inflammasome activation. Reduced abundance of PYCARD (ASC) and CASPASE-1 proteins in YS macrophages abrogated interleukin-1β production in response to canonical and non-canonical inflammasome activation. Conclusions: Macrophage ontogeny is associated with distinct cellular programs and immune response. Our findings contribute to the understanding of the regulation and programming of macrophage functions