Gene from a psoriasis susceptibility locus primes the skin for inflammation

Psoriasis is a common complex genetic disease characterized by hyperplasia and inflammation in the skin; however, the relative contributions of epidermal cells and the immune system to disease pathogenesis remain unclear. Linkage studies have defined a psoriasis susceptibility locus (PSORS4) on 1q21, the epidermal differentiation complex, which includes genes for small S100 calcium-binding proteins. These proteins are involved in extracellular and intracellular signaling during epithelial host defense, linking innate and adaptive immunity. Inflammation-prone psoriatic skin constitutively expresses elevated concentrations of S100A7 (psoriasin) and S100A15 (koebnerisin) in the epidermis. Here, we report that genetically modified mice expressing elevated amounts of doxycycline-regulated mS100a7a15 in skin keratinocytes demonstrated an exaggerated inflammatory response when challenged by exogenous stimuli such as abrasion (Koebner phenomenon). This immune response was characterized by immune cell infiltration and elevated concentrations of T helper 1 (T(H)1) and T(H)17 proinflammatory cytokines, which have been linked to the pathogenesis of psoriasis and were further amplified upon challenge. Both inflammation priming and amplification required mS100a7a15 binding to the receptor of advanced glycation end products (RAGE). mS100a7a15 potentiated inflammation by acting directly as a chemoattractant for leukocytes, further increasing the number of inflammatory cells infiltrating the skin. This study provides a pathogenetic psoriasis model using a psoriasis candidate gene to link the epidermis and innate immune system in inflammation priming, highlighting the S100A7A15-RAGE axis as a potential therapeutic target.     

Milk Fat Globule‐Epidermal Growth Factor 8 (MFG‐E8) Is a Novel Anti‐inflammatory Factor in Rheumatoid Arthritis in Mice and Humans

Milk fat globule‐epidermal growth factor 8 (MFG‐E8) is an anti‐inflammatory glycoprotein that mediates the clearance of apoptotic cells and is implicated in the pathogenesis of autoimmune and inflammatory diseases. Because MFG‐E8 also controls bone metabolism, we investigated its role in rheumatoid arthritis (RA), focusing on inflammation and joint destruction. The regulation of MFG‐E8 by inflammation was assessed in vitro using osteoblasts, in arthritic mice and in patients with RA. K/BxN serum transfer arthritis (STA) was applied to MFG‐E8 knock‐out mice to assess its role in the pathogenesis of arthritis. Stimulation of osteoblasts with lipopolysaccharide (LPS) and tumor necrosis factor (TNF)‐α downregulated the expression of MFG‐E8 by 30% to 35%. MFG‐E8‐deficient osteoblasts responded to LPS with a stronger production of pro‐inflammatory cytokines. In vivo, MFG‐E8 mRNA levels were 52% lower in the paws of collagen‐induced arthritic (CIA) mice and 24% to 42% lower in the serum of arthritic mice using two different arthritis models (CIA and STA). Similarly, patients with RA (n = 93) had lower serum concentrations of MFG‐E8 (–17%) compared with healthy controls (n = 140). In a subgroup of patients who had a moderate to high disease activity (n = 21), serum concentrations of MFG‐E8 rose after complete or partial remission had been achieved (+67%). Finally, MFG‐E8‐deficient mice subjected to STA exhibited a stronger disease burden, an increased number of neutrophils in the joints, and a more extensive local and systemic bone loss. This was accompanied by an increased activation of osteoclasts and a suppression of osteoblast function in MFG‐E8‐deficient mice. Thus, MFG‐E8 is a protective factor in the pathogenesis of RA and subsequent bone loss. Whether MFG‐E8 qualifies as a novel biomarker or therapeutic target for the treatment of RA is worth addressing in further studies. © 2015 American Society for Bone and Mineral Research.     

Apathy,cognitive dysfunction and impaired social cognition in a patient with bilateral thalamic infarction

We describe the case of a patient with bilateral thalamic lesions due to brain infarcts in the paramedian thalamic artery territories. The patient demonstrated symptoms of apathy (e.g., loss of initiative and interest in others, poor motivation, flattened affect). Neuropsychological assessment 3 and 5 years post-infarct revealed severe deficits in verbal and non-verbal immediate and delayed memory, attention, and executive functioning, with minimal improvement over time. Also, he demonstrated difficulties in social cognition (i.e., perception of facial expressions of others and of sarcasm). These findings are discussed and interpreted in light of current theories regarding the neurobiological substrate of apathy.     

The role of innate immunity in the regulation of brown and beige adipogenesis

The adipose tissue (AT) is multifunctional, acting as an endocrine tissue and participating in the regulation of the organism’s homeostasis. Metabolic, endocrine and inflammatory mechanisms are tightly intertwined within the AT, regulating its function. Disruption of the equilibrium among these mechanisms leads to pathologies, the most common being obesity-related insulin resistance. Two types of AT exist, the white and the brown AT. Traditionally the white AT (WAT) was thought to store energy in the form of lipids, while the brown AT (BAT) was known to mediate heat generation. Recently, the ‘brite’ or ‘beige’ AT was identified, which is localized predominantly in subcutaneous WAT, but shares functional features with the BAT and is capable of heat production. The major stimulus triggering beige and brown adipogenesis is cold exposure and catecholamine signalling. However, several further signals and mechanisms exist, which can orchestrate and fine-tune beige and brown AT function. Immune cells and inflammation have emerged as regulators of beige and brown AT function. The present review will focus on the recently identified crosstalk between innate immunity and the regulation of beige and brown adipogenesis.     

Multistage nanoparticle delivery system for deep penetration into tumor tissue

Current Food and Drug Administration-approved cancer nanotherapeutics, which passively accumulate around leaky regions of the tumor vasculature because of an enhanced permeation and retention (EPR) effect, have provided only modest survival benefits. This suboptimal outcome is likely due to physiological barriers that hinder delivery of the nanotherapeutics throughout the tumor. Many of these nanotherapeutics are ≈ 100 nm in diameter and exhibit enhanced accumulation around the leaky regions of the tumor vasculature, but their large size hinders penetration into the dense collagen matrix. Therefore, we propose a multistage system in which 100-nm nanoparticles "shrink" to 10-nm nanoparticles after they extravasate from leaky regions of the tumor vasculature and are exposed to the tumor microenvironment. The shrunken nanoparticles can more readily diffuse throughout the tumor's interstitial space. This size change is triggered by proteases that are highly expressed in the tumor microenvironment such as MMP-2, which degrade the cores of 100-nm gelatin nanoparticles, releasing smaller 10-nm nanoparticles from their surface. We used quantum dots (QD) as a model system for the 10-nm particles because their fluorescence can be used to demonstrate the validity of our approach. In vitro MMP-2 activation of the multistage nanoparticles revealed that the size change was efficient and effective in the enhancement of diffusive transport. In vivo circulation half-life and intratumoral diffusion measurements indicate that our multistage nanoparticles exhibited both the long circulation half-life necessary for the EPR effect and the deep tumor penetration required for delivery into the tumor's dense collagen matrix.     

Regulation of LFA-1-dependent inflammatory cell recruitment by Cbl-b and 14-3-3 proteins

Inside-out signaling regulation of the beta2-integrin leukocyte function-associated antigen-1 (LFA-1) by different cytoplasmic proteins, including 14-3-3 proteins, is essential for adhesion and migration of immune cells. Here, we identify a new pathway for the regulation of LFA-1 activity by Cbl-b, an adapter molecule and ubiquitin ligase that modulates several signaling pathways. Cbl-b-/- mice displayed increased macrophage recruitment in thioglycollate-induced peritonitis, which was attributed to Cbl-b deficiency in macrophages, as assessed by bone marrow chimera experiments. In vitro, Cbl-b-/- bone marrow-derived mononuclear phagocytes (BMDMs) displayed increased adhesion to endothelial cells. Activation of LFA-1 in Cbl-b-deficient cells was responsible for their increased endothelial adhesion in vitro and peritoneal recruitment in vivo, as the phenotype of Cbl-b deficiency was reversed in Cbl-b-/-LFA-1-/- mice. Consistently, LFA-1-mediated adhesion of BMDM to ICAM-1 but not VLA-4-mediated adhesion to VCAM-1 was enhanced by Cbl-b deficiency. Cbl-b deficiency resulted in increased phosphorylation of T758 in the beta2-chain of LFA-1 and thereby in enhanced association of 14-3-3beta protein with the beta2-chain, leading to activation of LFA-1. Consistently, disruption of the 14-3-3/beta2-integrin interaction abrogated the enhanced ICAM-1 adhesion of Cbl-b-/- BMDMs. In conclusion, Cbl-b deficiency activates LFA-1 and LFA-1-mediated inflammatory cell recruitment by stimulating the interaction between the LFA-1 beta-chain and 14-3-3 proteins.     

Hypothalamo-pituitary and immune-dependent adrenal regulation during systemic inflammation

Inflammation-related dysregulation of the hypothalamic–pituitary–adrenal (HPA) axis is central to the course of systemic inflammatory response syndrome or sepsis. The underlying mechanisms, however, are not well understood. Initial activation of adrenocortical hormone production during early sepsis depends on the stimulation of hypothalamus and pituitary mediated by cytokines; in late sepsis, there is a shift from neuroendocrine to local immune–adrenal regulation of glucocorticoid production. Therefore, the modulation of the local immune–adrenal cross talk, and not of the neuroendocrine circuits involved in adrenocorticotropic hormone production, may be more promising in the prevention of the adrenal insufficiency associated with prolonged sepsis. In the present work, we investigated the function of the crucial Toll-like receptor (TLR) adaptor protein myeloid differentiation factor 88 (MyD88) in systemic and local activation of adrenal gland inflammation and glucocorticoid production mediated by lipopolysachharides (LPSs). To this end, we used mice with a conditional MyD88 allele. These mice either were interbred with Mx1 Cre mice, resulting in systemic MyD88 deletion, predominantly in the liver and hematopoietic system, or were crossed with Akr1b7 Cre transgenic mice, resulting thereby in deletion of MyD88, which was adrenocortical-specific. Although reduced adrenal inflammation and HPA-axis activation mediated by LPS were found in Mx1^Cre+-MyD88^fl/fl mice, adrenocortical-specific MyD88 deletion did not alter the adrenal inflammation or HPA-axis activity under systemic inflammatory response syndrome conditions. Thus, our data suggest an important role of immune cell rather than adrenocortical MyD88 for adrenal inflammation and HPA-axis activation mediated by LPS.Sepsis and septic shock are major causes of death in intensive-care units worldwide and show an increasing incidence (1). In sepsis, excessive, uncontrolled activation of the immune system is harmful to the host and leads to multiorgan failure and death. Adrenal glucocorticoid production plays a beneficial role in response to systemic inflammation by counteracting hyperactivation of the immune system. However, in many critically ill patients, this homeostatic activation of adrenocortical hormone secretion is impaired (2). It has been estimated that 60% of critically ill patients show an abnormal adrenal glucocorticoid response to administration of exogenous adrenocorticotropic hormone (ACTH) (3).Adrenal hormone production in sepsis is thought to be regulated by cytokines that elevate hypothalamic corticotropin releasing hormone (CRH) levels. CRH, in turn, produces the release of pituitary ACTH—the main regulator of synthesis of adrenal glucocorticoid hormones (4). It is generally accepted that pattern-recognition receptors such as Toll-like receptors (TLRs) play a substantial role in hypothalamic–pituitary–adrenal (HPA) axis activation induced by pathogens. This activation, in turn, may be attributable to functions of these receptors on both myeloid and nonmyeloid cells (e.g., endothelial cells of the blood–brain barrier) (5). Furthermore, besides activation of immune cells, bacterially derived TLR ligands, such as lipopolysaccharides (LPSs), can directly affect both neuronal cells (6) and steroid-producing cells in the adrenal gland (7).Although most LPS actions on adrenal-gland glucocorticoid production have been attributed to activation of HPA axis by cytokines at the level of the hypothalamus and pituitary gland, a critical involvement of an intrinsically regulated immune–adrenal cross talk has also been implicated. In fact, we and others have demonstrated that adrenocortical cells express several TLRs and secrete multiple proinflammatory cytokines such as tumor necrosis factor (TNF) and interleukin (IL)6 in response to bacterial endotoxin stimulation (7). Using mice deficient in either TLR2 or TLR4, we demonstrated a critical function of these receptors as regulators of the immune–adrenal cross talk during LPS-mediated systemic inflammation. The absence of these receptors correlates with increased basal levels of either ACTH (for TLR2) or corticosterone (for TLR4) and impaired adrenal glucocorticoid responses to injection of LPS (8, 9). However, the exact contributions of the TLRs on different cell types to inflammation-mediated adrenal dysfunction as well as to activation of HPA axis are not entirely clear. Furthermore, because both TLR2 and TLR4 were shown to be involved in early neurogenesis (10), the deficiency of these receptors from the very early developmental stage might potentially influence the basal function of the HPA axis. Myeloid differentiation factor 88 (MyD88) is a central component of the signaling pathway of TLRs, promoting nuclear factor kappa B (NF-κB) activation in response to LPS or IL1 β. Thus, blocking of MyD88-dependent signaling in a cell-specific manner represents an attractive experimental tool to address the aforementioned issue.These data and observations prompted us to investigate the role of systemic and local adrenal TLR signaling in the activation of the adrenal glucocorticoid response to stress and regulation of the immune–adrenal cross talk during the systemic inflammatory response syndrome (SIRS) phenomenon. Our results suggest that immune cells, rather than adrenal cells, are the major regulators of the systemic and intraadrenal inflammatory response to LPS. However, the full HPA axis activation in SIRS is not entirely dependent on systemic TLR signaling.