Targeting the stromal microenvironment in chronic inflammation

Abstract

A characteristic feature of chronic inflammatory reactions is their persistence and predilection for certain sites. The molecular basis for such tissue tropism (as, for example, seen with metastatic spread) has until recently remained obscure, but recent studies have strongly implicated tissue-resident, stromal cells, such as macrophages, endothelial cells and fibroblasts. These cell types make attractive therapeutic targets as they help define the three-dimensional structure of tissues and are key orchestrators of the inflammatory infiltrate. Most current anti-inflammatory therapies target immune cells in an attempt to inhibit the production of pro-inflammatory mediators; however, an equally important target is the active induction of anti-inflammatory mediators involved in the resolution of inflammation. Recent work suggests that stromal cells are an important source of these mediators. Targeting of multiple signals may be required to inhibit tissue damage associated with inflammatory disease. Cells of the monocyte lineage are present as tissue-resident cells and interact closely with other stromal populations. These cells form an ideal target for modulation of the inflammatory environment as, in some cases, they appear to induce tissue repair. Therapeutic manipulation of the stromal microenvironment has been particularly effective in treating cancer and is likely to provide a novel method to achieve improved control of chronic inflammatory disease.

Figure 1

Leukocyte–stromal interactions in chronic inflammatory disease. The molecular basis by which leukocytes leave the circulation and migrate across endothelium has been well studied; stromal and lymphatic trafficking remain less well understood. Leukocytes captured by selectin/ligand interactions roll, sampling the presence of chemokines and other activation markers on the endothelium and associated matrix proteins. Infiltrating cells undergo firm adhesion then migrate through the endothelial layer following chemokine gradients into the tissue stroma. Possible therapeutic targets here include inhibition of angiogenesis using VEGF blockade, and blockade of specific chemokines and their receptors including CXCL12/CXCR4. Alternatively, depletion of precursor cell populations such as fibrocytes and endothelial precursors offers a means to control stromally mediated inflammation and angiogenesis. Within the stroma, some cells are destined to die, such as neutrophils. Others such as monocytes can differentiate into cells destined to die, such as macrophages; others might proliferate. Potential targets within the stroma include deletion of specific monocyte/macrophage populations with a pathological role, as suggested by work in models of liver fibrosis (see text). Blockade of novel cytokines and chemokines, and also of stromal/leukocyte cell-mediated interactions via molecules such as CD40, have immediate therapeutic potential. Also potentially important is blockade of the transdifferentiation of tissue resident cells such as monocytes into pathogically important macrophage populations, or their accelerated apoptosis. Those cells destined to recirculate must follow other chemokine gradients towards the lymphatic endothelium and exit from the tissue towards draining lymph nodes. The endothelium regulates entry; the stroma regulates proliferation, survival and differentiation; and the lymphatics regulate exit.

Figure 2

Divergence of macrophage function in fibrotic liver disease. During fibrosis progression (rising solid line on graph), TGF-β1 is a potential macrophage-derived stimulator of stellate cell activation. Depletion of macrophages during this phase results in decreased scarring and fewer myofibroblasts, with decreased inflammation (small red arrow). During fibrosis regression (falling solid line on graph), stellate cell apoptosis can occur under the influence of macrophage-derived TRAIL. Depletion of macrophages early during fibrosis regression results in sustained inflammation and accumulation of scarring matrix (large red arrow). Hepatic macrophages thus have divergent effects on liver stellate cell activation in models of fibrosis.