Springer Science and Business Media LLC

Recently published studies in multiple sclerosis (MS) and experimental autoimmune encephalomyelitis (EAE) have demonstrated an association between the development of demyelinating plaques and the accumulation of Th17 cells in the central nervous system and periphery. However, a causal relationship has been difficult to establish. In fact, in reports published thus far, interleukin (IL)-17A deficiency or neutralization in vivo attenuates, but does not completely abrogate, EAE. There is growing evidence that clinically similar forms of autoimmune demyelinating disease can be driven by myelin-specific T cells of distinct lineages with different degrees of dependence on IL-17A production to achieve their pathological effects. While such observations cast doubts about the potential therapeutic efficacy of Th17 blocking agents in MS, the collective data suggest that IL-17A expression in peripheral blood mononuclear cells could serve as a surrogate biomarker of neuroinflammation and plaque formation and be a useful outcome measure for future clinical trials.

Among other functions, the skin serves as the barrier against the environment and provides vital protection from physical or chemical harm and from infection. Skin cells express the aryl hydrocarbon receptor (AHR), a ligand-activated transcription factor and sensor of environmental chemicals; at the same time, AHR ligands are abundant in skin from exogenous or endogenous sources. For example, solar radiation, in particular ultraviolet (UV) B, generates AHR ligands from tryptophan in the skin. Recent evidence has shown that AHR is involved in the (patho)physiology of skin including the regulation of skin pigmentation, photocarcinogenesis, and skin inflammation. We here provide a state-of-the-art summary of work which relates to the role of the AHR in (1) adaptive responses against environmental challenges such as UVB or topical chemicals and (2) intrinsic developmental roles for homeostasis of skin cells and (3) skin immunity. We also discuss the existing evidence that AHR antagonists or AHR ligands may be used for the prevention and/or treatment of skin disease.

Monogenic autoinflammatory diseases are defined as a group of conditions with a clinical and biological inflammatory syndrome but little or no evidence of autoimmunity. Over 17 years have passed since the discovery of the first autoinflammatory gene, MEFV, responsible for familial Mediterranean fever. Substantive progress has been made since then, highlighting the key role of the inflammasome in the maintenance of the cell homeostasis but also unravelling new pathophysiological pathways involved in these diseases. The history of autoinflammatory gene discovery demonstrates the powerfulness of next-generation sequencing approaches in linking inflammatory disorders with various overlapping phenotypes. It can be easily anticipated that new genes will be exponentially identified in the coming years. Integrating these new concepts should help to promote personalized patient care through novel therapeutic opportunities.

Spatiotemporal control of leukocyte dynamics within tissues is critical for successful innate and adaptive immune responses. Homeostatic trafficking and coordinated infiltration into and within sites of inflammation and infection rely on signaling in response to extracellular cues that in turn controls a variety of intracellular protein networks regulating leukocyte motility, migration, chemotaxis, positioning, and cell–cell interaction. In contrast to mesenchymal cells, leukocytes migrate in an amoeboid fashion by rapid cycles of actin polymerization and actomyosin contraction, and their migration in tissues is generally referred to as low adhesive and nonproteolytic. The interplay of actin network expansion, contraction, and adhesion shapes the exact mode of amoeboid migration, and in this review, we explore how leukocyte subsets potentially harness the same basic biomechanical mechanisms in a cell-type-specific manner. Most of our detailed understanding of these processes derives from in vitro migration studies in three-dimensional gels and confined spaces that mimic geometrical aspects of physiological tissues. We summarize these in vitro results and then critically compare them to data from intravital imaging of leukocyte interstitial migration in mouse tissues. We outline the technical challenges of obtaining conclusive mechanistic results from intravital studies, discuss leukocyte migration strategies in vivo, and present examples of mode switching during physiological interstitial migration. These findings are also placed in the context of leukocyte migration defects in primary immunodeficiencies. This overview of both in vitro and in vivo studies highlights recent progress in understanding the molecular and biophysical mechanisms that shape robust leukocyte migration responses in physiologically complex and heterogeneous environments.

Only a few decades ago, students of the pathophysiology of cardiovascular disease paid little heed to the involvement of inflammation and immunity. Multiple lines of evidence now point to the participation of innate and adaptive immunity and inflammatory signaling in a variety of cardiovascular conditions. Hence, interest has burgeoned in this intersection. This review will focus on the contribution of innate immunity to both acute injury to the heart muscle itself, notably myocardial infarction, and to chronic inflammation in the artery wall, namely atherosclerosis, the cause of most myocardial infarctions. Our discussion of the operation of innate immunity in cardiovascular diseases will focus on functions of the mononuclear phagocytes, with special attention to emerging data regarding the participation of different functional subsets of these cells in cardiovascular pathophysiology.

With obesity and type 2 diabetes prevalence steadily increasing and no effective means in sight to support the population in obtaining and maintaining stable weight loss, there is an imminent need for pharmacological therapy to treat and prevent type 2 diabetes. Current anti-diabetic treatment is symptomatic, and very few drugs have both a strong preclinical rationale and clinical proof-of-principle as therapies targeting pathogenic processes in type 2 diabetes. The emerging appreciation of low-grade inflammation as a significant cause of insulin resistance and beta cell failure warrants exploring anti-inflammatory compounds as drug candidates. Since recent studies have demonstrated considerable phenotypic heterogeneity in the type 2 diabetic syndrome, the concept of one drug fits all is naïve, and biomarkers for the selection of type 2 diabetes subtypes for differentiated treatment based on genetic and pathogenic stratification are urgently needed. Biologics antagonizing the master pro-inflammatory cytokine interleukin-1 is one of the few principles specifically targeting low-grade inflammation in type 2 diabetes. Although early phase II studies were encouraging, subsequent underpowered studies and phase III studies designed primarily with cardiovascular endpoints have discredited the potential of anti-interleukin-1 approaches to treat the subgroup of patients that may benefit from this treatment. In this meta-analysis of 2921 individuals from eight phase I–IV studies, we demonstrate a significant overall HbA1c-lowering effect of interleukin-1 antagonism. Meta-regression analyses demonstrated a significant correlation between baseline C-reactive protein and C-peptide, and HbA1c outcome. The identification of further biomarkers for future clinical trials to define the potential of anti-interleukin-1 therapies in type 2 diabetes is urgently needed.

Obesity is associated with various metabolic and cardiovascular diseases caused by chronic, low-grade inflammation that is initially observed in obese adipose tissue. In addition, many etiological studies in humans have shown a strong correlation between obesity and inflammatory autoimmune diseases. In this review, we focus on the involvement of apoptosis inhibitor of macrophage (AIM), a macrophage-derived blood protein, in both types of immune response. Through differential mechanisms, AIM thereby plays key roles in the pathogenesis of atherosclerosis, metabolic diseases, and obesity-associated autoimmune diseases. Thus, the regulation of blood AIM levels or AIM function has the potential to serve as a next-generation therapy against these inflammatory diseases brought about by modern lifestyle.