To get to the site of inflammation, leukocytes must first adhere to and traverse the blood-vessel wall, events that occur in a cascade-like manner. But what are the exact steps in this cascade and what molecules are involved?

Getting to the site of inflammation: the leukocyte adhesion cascade updated

The memory T cell pool functions as a dynamic repository of antigen-experienced T lymphocytes that accumulate over the lifetime of the individual. Recent studies indicate that memory T lymphocytes contain distinct populations of central memory (TCM) and effector memory (TEM) cells characterized by distinct homing capacity and effector function. This review addresses the heterogeneity of TCM and TEM, their differentiation stages, and the current models for their generation and maintenance in humans and mice.

Central Memory and Effector Memory T Cell Subsets: Function, Generation, and Maintenance

Wound healing is an evolutionarily conserved, complex, multicellular process that, in skin, aims at barrier restoration. This process involves the coordinated efforts of several cell types including keratinocytes, fibroblasts, endothelial cells, macrophages, and platelets. The migration, infiltration, proliferation, and differentiation of these cells will culminate in an inflammatory response, the formation of new tissue and ultimately wound closure. This complex process is executed and regulated by an equally complex signaling network involving numerous growth factors, cytokines and chemokines. Of particular importance is the epidermal growth factor (EGF) family, transforming growth factor beta (TGF-beta) family, fibroblast growth factor (FGF) family, vascular endothelial growth factor (VEGF), granulocyte macrophage colony stimulating factor (GM-CSF), platelet-derived growth factor (PDGF), connective tissue growth factor (CTGF), interleukin (IL) family, and tumor necrosis factor-alpha family. Currently, patients are treated by three growth factors: PDGF-BB, bFGF, and GM-CSF. Only PDGF-BB has successfully completed randomized clinical trials in the Unites States. With gene therapy now in clinical trial and the discovery of biodegradable polymers, fibrin mesh, and human collagen serving as potential delivery systems other growth factors may soon be available to patients. This review will focus on the specific roles of these growth factors and cytokines during the wound healing process.

https://onlinelibrary.wiley.com/doi/pdf/10.1111/j.1524-475X.2008.00410.x

Growth factors and cytokines in wound healing.

Endothelial Cells in Physiology and in the Pathophysiology of Vascular Disorders

MSCs are nonhematopoietic stromal cells that are capable of differentiating into, and contribute to the regeneration of, mesenchymal tissues such as bone, cartilage, muscle, ligament, tendon, and adipose. MSCs are rare in bone marrow, representing approximately 1 in 10,000 nucleated cells. Although not immortal, they have the ability to expand manyfold in culture while retaining their growth and multilineage potential. MSCs are identified by the expression of many molecules including CD105 (SH2) and CD73 (SH3/4) and are negative for the hematopoietic markers CD34, CD45, and CD14. The properties of MSCs make these cells potentially ideal candidates for tissue engineering. It has been shown that MSCs, when transplanted systemically, are able to migrate to sites of injury in animals, suggesting that MSCs possess migratory capacity. However, the mechanisms underlying the migration of these cells remain unclear. Chemokine receptors and their ligands and adhesion molecules play an important role in tissue-specific homing of leukocytes and have also been implicated in trafficking of hematopoietic precursors into and through tissue. Several studies have reported the functional expression of various chemokine receptors and adhesion molecules on human MSCs. Harnessing the migratory potential of MSCs by modulating their chemokine-chemokine receptor interactions may be a powerful way to increase their ability to correct inherited disorders of mesenchymal tissues or facilitate tissue repair in vivo. The current review describes what is known about MSCs and their capacity to home to tissues together with the associated molecular mechanisms involving chemokine receptors and adhesion molecules.

https://stemcellsjournals.onlinelibrary.wiley.com/doi/epdf/10.1634/stemcells.2007-0197

Concise review: mesenchymal stem cells: their phenotype, differentiation capacity, immunological features, and potential for homing.

Transcytosis and Surface Presentation of IL-8 by Venular Endothelial Cells

Interleukin-8 stimulates calcium transients and promotes epidermal cell proliferation.

We have previously reported that mice lacking inducible nitric oxide synthase (NOS2) developed
enhanced Th1 cell responses. We now investigated the mechanism by which NO modulates
Th1 cells differentiation. Peritoneal macrophages from NOS2-deficient mice infected
with Leishmania major in vivo or stimulated with IFN- + or lipopolysaccharide (LPS) in vitro
produced significantly higher levels of IL-12 than those from heterozygous or wild-type mice.
A macrophage cell line, J774, produced significant amounts of IL-12 following activation
with LPS, or LPS plus IFN- + . This could be markedly enhanced by the NOS inhibitor L-NG
monomethyl arginine (L-NMMA), but profoundly inhibited by the NO-generating compound
S-nitroso-N-acetyl-penicillamine (SNAP). The effect of NO in this system is selective, since
SNAP enhanced and L-NMMA decreased TNF- § synthesis by LPS-activated J774 cells. The
differential effect of NO on IL-12 and TNF- § is at the transcriptional level and is activation
dependent. Since IL-12 is a major inducer of Th1 cells which produce IFN- + that can activate
macrophages to produce IL-12, our data demonstrate that NO can be an inhibitor of this
feedback loop, preventing the excessive amplification of Th1 cells which are implicated in a
range of immunopathologies.

Nitric oxide regulates Th1 cell development through the inhibition of IL-12 synthesis by macrophages

Cyclic Nucleotide Phosphodiesterase 4 Subtypes Are Differentially Expressed by Primary Keratinocytes and Human Epidermoid Cell Lines

The ability of interleukin-1 (IL-1) to activate epidermal cell populations supports its role as a key cytokine in the pathogenesis of a number of inflammatory skin diseases. In the present study, we have examined the effect of interferon (IFN)-gamma on the expression of the IL-1 beta gene in mouse RAW 264.7 macrophages activated by lipopolysaccharide (LPS) plus tumor necrosis factor (TNF)-alpha. Incubation of macrophages with both LPS and TNF-alpha resulted in the expression of both IL-1 beta and inducible nitric oxide synthase (iNOS) mRNA transcripts and increased the release of IL-1 beta protein and nitrite production in culture supernatants. Addition of IFN-gamma up-regulated the expression of the iNOS gene in cells activated by LPS + TNF-alpha, but significantly suppressed the induction of IL-1 beta gene expression in a dose-dependent manner. The suppression required neither de novo protein synthesis nor involved destabilization of the mRNA transcripts. Together, these findings suggest that IFN-gamma can be an important regulatory cytokine in a chronic inflammatory site and may explain its purported anti-inflammatory effects in certain dermatological diseases.

Charles Lam

Papers

Transcytosis and Surface Presentation of IL-8 by Venular Endothelial Cells

Interleukin-8 stimulates calcium transients and promotes epidermal cell proliferation.

Nitric oxide regulates Th1 cell development through the inhibition of IL-12 synthesis by macrophages

Cyclic Nucleotide Phosphodiesterase 4 Subtypes Are Differentially Expressed by Primary Keratinocytes and Human Epidermoid Cell Lines

Selective inhibition of interleukin-1β gene expression in activated RAW 264.7 macrophages by interferon-γ