Reviews & Analysis

Complement is intricately involved in inflammatory processes, yet the mechanisms that modulate the actions of its key mediator C5a are poorly understood. A new study uncovers a molecular partnership between three neutrophil receptors in the recognition of differentially glycated immune complexes and sheds light on regulatory processes in autoimmune and inflammatory disorders (pages 1401–1406).

Neutrophils release extracellular DNA traps (NETs) to capture and kill pathogens. A recent study shows that live neutrophils are simultaneously able to form NETs while crawling and phagocytosing and can even combat bacteria after loss of their nuclear DNA (pages 1386–1393).

Hepatic fibrosis results from chronic liver injury due to viral infection, metabolic diseases, toxins such as alcohol, or immune attack. Now, a heritable epigenetic determinant of fibrosis has been uncovered, providing evidence that sperm from male rats with liver injury confers reduced fibrosis in their male offspring (pages 1369– 1377).

A better understanding of mechanisms involved in regulation of drug sensitivity is crucial for improved cancer treatment. New studies show that cells of the tumor microenvironment modulate the response of cancer cells to chemotherapy and targeted therapies through production of secreted factors (pages 1359–1368).

A new mechanism regulating pathological angiogenesis has been identified that involves the activation of ataxia-telangiectasia mutated (Atm) kinase in response to reactive oxygen species. Importantly, this Atm-dependent pathway is specifically activated in pathological, but not in normal, angiogenesis, suggesting that it could be therapeutically targeted in diseases associated with pathological angiogenesis (pages 1208–1216).

There is currently much interest in dissecting the mechanisms of tumor immunity. A new study shows that a subset of CD4⁺ T cells that produce the cytokine interleukin-9 (IL-9) mediate inhibition of melanoma growth in mice and that analogous IL-9–producing T cells are present in human skin (pages 1248–1253). Could such cells be manipulated to develop new therapeutic strategies for melanoma?

Malignant gliomas are devastating, uniformly fatal cancers for which current therapies remain palliative. A new study in mice shows that neural precursor cells, abundant in neonatal brains, release a fatty acid factor that induces glioma cell death through the activation of TRPV1 channels, prolonging survival and potentially uncovering a new treatment strategy (pages 1232–1238).

Prolonged febrile seizures in young children have long been suspected to lead to temporal lobe epilepsy, but how this occurs has been unclear. A new study (pages 1271–1278) in rats showing that febrile seizures induce aberrant migration of cells in the temporal lobe suggests this may be a crucial component in the development of epilepsy.

Fibrosis is omnipresent and contributes to a substantial proportion of all natural deaths. A recent study (pages 1262–1270) provides evidence that the mysterious perivascular cell, also known as the pericyte, is the cell type responsible for fibrotic disease in skin and skeletal muscle.

The liver secretory protein fetuin-A (FetA) is now shown to act as an adaptor protein between free fatty acids (FFAs) and Toll-like receptor 4 (TLR4), providing the missing link between FFAs and chronic low-grade inflammation that impairs insulin sensitivity (pages 1279–1285).

This review describes how the evolving field of neuroepigenetics can provide a new understanding of the mechanisms involved in neurodevelopmental and neurodegenerative disorders. It also discusses how epigenetic therapeutics that have been approved for other diseases, such as cancer, could be useful in modulating neurological conditions associated with epigenetic abnormalities.

The enthesis is the region at the junction between tendon and bone and has been suggested to be a key target in spondyloarthritic diseases. This zone is now shown to contain a unique population of resident T cells, which, when activated by the cytokine interleukin-23 (IL-23), can promote pathogenesis that is characteristic of spondyloarthritis (pages 1069–1076).

A recent study highlights the potential of therapeutically modulating the endogenous miRNA pathway in a mouse model of spinal and bulbar muscular atrophy (SBMA). The overexpression of a naturally occurring miRNA led to the downregulation of the mutant androgen receptor transcript as well as the polyglutamine-containing protein it encodes, both of which may contribute to pathogenesis in SBMA (pages 1136–1141).

MicroRNAs (miRNAs) have emerged as crucial mediators of human disease, but their roles in autoimmunity have only recently been appreciated. A new study using mouse and human tissues from various interleukin-17 (IL-17)-related autoimmune disorders now shows that miRNA-23b is a central regulator of inflammation in resident tissue cells during autoimmunity (pages 1077–1086).

Whereas the adaptive immune response is essential for control and clearance of hepatitis B virus infection, the importance of the early innate immune response is controversial and the players involved are poorly defined. A new study shows that activation of natural killer T cells by infected hepatocytes is crucial for the early control of this disease (pages 1060–1068).

Endometriosis occurs when estrogen-sensitive endometrial cells that are shed to distal sites manage to attach and survive in a foreign, inflammatory environment. A new study reports a unique interaction between a cleaved form of steroid receptor coactivator 1 (SRC-1) and caspase 8 that blocks apoptosis in endometriotic cells, allowing them to survive (pages 1102–1111).

Acute exposure to ionizing radiation can cause lethality via severe damage to the hematopoietic system. A new study shows that infusion of the anticoagulants thrombomodulin or activated protein C reduces radiation toxicities and improves survival (pages 1123–1129).

Fibrosis is a key aspect of many chronic inflammatory diseases and can affect almost every tissue in the body. This review discusses recent advances in our understanding of the mechanisms of fibrosis, focusing on the innate and adaptive immune responses. It also describes how some of these crucial pathogenic pathways are being therapeutically targeted in the clinic.

Genomic technologies are being rapidly applied to the area of prenatal diagnosis, and many genomic prenatal tests have already been transitioned to the clinic. Diana Bianchi reviews these advances in prentatal diagnosis and highlights the challenges in bringing them to the clinic. She also discusses how genomic and transcriptomic technologies might be applied to understand the pathology of fetal diseases and disorders of pregnancy and, perhaps, develop new therapies for these conditions.

Kaposi's sarcoma–associated herpesvirus is a major oncogenic virus that has been implicated in human cancers. A new study identifies ephrin receptor A2 as a key host receptor for this virus that permits infection of endothelial cells (pages 961–966).