Christopher D. Buckley

Resolution of inflammation: state of the art, definitions and terms

A recent focus meeting on Controlling Acute Inflammation was held in London, April 27–28, 2006, organized by D.W. Gilroy and S.D. Brain for the British Pharmacology Society. We concluded at the meeting that a consensus report was needed that addresses the rapid progress in this emerging field and details how the specific study of resolution of acute inflammation provides leads for novel anti‐inflammatory therapeutics, as well as defines the terms and key components of interest in the resolution process within tissues as appreciated today. The inflammatory response protects the body against infection and injury but can itself become dysregulated with deleterious consequences to the host. It is now evident that endogenous biochemical pathways activated during defense reactions can counter‐regulate inflammation and promote resolution. Hence, resolution is an active rather than a passive process, as once believed, which now promises novel approaches for the treatment of inflammation‐associated diseases based on endogenous agonists of resolution.—Serhan, C. N., Brain, S. D., Buckley, C. D., Gilroy, D. W., Haslett, C., ONeill, L. A. J., Perretti, M., Rossi, A. G., Wallace, J. L. Resolution of inflammation: state of the art, definitions and terms. FASEB J. 21, 325–332 (2007)

Mesenchymal stem cells: the fibroblasts’ new clothes?

This review article presents the evidence that mesenchymal stem cells and fibroblasts share much more in common than previously recognized. Mesenchymal stem cells are adherent stromal cells, initially isolated from the bone marrow, characterized by their ability to differentiate into mesenchymal tissues such as bone, cartilage and fat. They have also been shown to suppress immune responses in vitro. Because of these properties, mesenchymal stem cells have recently received a very high profile. Despite the dramatic benefits reported in early phase clinical trials, their functions remain poorly understood. Particularly, several questions remain concerning the origin of mesenchymal stem cells and their relationship to other stromal cells such as fibroblasts. Whereas clear gene expression signatures are imprinted in stromal cells of different anatomical origins, the anti-proliferative effects of mesenchymal stem cells and fibroblasts and their potential to differentiate appear to be common features between these two cell types. In this review, we summarize recent studies in the context of historical and often neglected stromal cell literature, and present the evidence that mesenchymal stem cells and fibroblasts share much more in common than previously recognized.

Tissue stroma as a regulator of leukocyte recruitment in inflammation

The stromal milieu (cellular and matrix components) helps establish tissue “address‐codes” that direct leukocyte behavior in inflamed tissue. Coordinated interactions among the stroma, leukocytes, and ECs dictate which leukocytes are recruited, whether they are retained within the inflamed site, and how long they survive. Herein, we discuss how the stromal milieu influences the leukocyte recruitment cascade. Moreover, we explore how corruption of the stromal phenotype in chronic inflammatory diseases contributes to undesired, continuous recruitment of leukocytes. Emerging complex, multicellular, multilayered (co‐)culture models are now addressing the molecular circuitry involved in regulating stromal organization during inflammation. Understanding context‐specific changes in pro‐ or anti‐inflammatory agents derived from the stroma, such as IL‐6 (and its cofactors), is important for the generation of therapeutic strategies that restore the balance between recruitment and clearance of the inflammatory infiltrate in chronic disease.

The Role of Platelet-Endothelial Cell Adhesion Molecule-1 in Atheroma Formation Varies Depending on the Site-Specific Hemodynamic Environment

Objective—Polymorphisms in the platelet-endothelial cell adhesion molecule (PECAM-1)-1 gene are linked to increased risk of coronary artery disease. Because PECAM-1 has been demonstrated to form a mechanosensory complex that can modulate inflammatory responses in murine arterial endothelial cells, we hypothesized that PECAM-1 contributes to atherogenesis in a shear-dependent and site-specific manner. Approach and Results—ApoE–/– mice that were wild-type, heterozygous, or deficient in PECAM-1 were placed on a high-fat diet. Detailed analysis of the aorta at sites with differing hemodynamics revealed that PECAM-1–deficient mice had reduced disease in areas of disturbed flow, whereas plaque burden was increased in areas of steady, laminar flow. In concordance with these observations, bone marrow chimera experiments revealed that hematopoietic PECAM-1 resulted in accelerated atheroma formation in areas of laminar and disturbed flow, however endothelial PECAM-1 moderated disease progression in areas of high sheer stress. Moreover, using shear stress–modifying carotid cuffs, PECAM-1 was shown to promote macrophage recruitment into lesions developing in areas of low shear stress. Conclusions—PECAM-1 on bone marrow cells is proatherogenic irrespective of the hemodynamic environment, however endothelial cell PECAM-1 is antiatherogenic in high shear environments. Thus, targeting this pathway therapeutically would require a cell-type and context-specific strategy.

Anti-modified citrullinated vimentin (MCV) antibodies in patients with very early synovitis

Anti-modified citrullinated vimentin (MCV) antibodies in patients with very early synovitis

CD248 expression on mesenchymal stromal cells is required for post-natal and infection-dependent thymus remodelling and regeneration

The role of mesenchymal stromal cells (MSCs) in regulating immune responses in the thymus is currently unclear. Here we report the existence and role of a MSC population in the thymus that expresses the pericyte and MSC marker CD248 (endosialin). We show using a CD248‐deficient mouse model, that CD248 expression on these cells is required for full post‐natal thymus development and regeneration post‐Salmonella infection. In CD248−/− mice the thymus is hypocellular and regeneration is poorer, with significant loss of all thymocyte populations. This identifies the requirement of CD248 to maintain optimal thymic cellularity post‐partum and infection.