Capillary and arteriolar pericytes attract innate leukocytes exiting through venules and 'instruct' them with pattern-recognition and motility programs

Abstract

Coordinated navigation within tissues is essential for cells of the innate immune system to reach the sites of inflammatory processes, but the signals involved are incompletely understood. Here we demonstrate that NG2(+) pericytes controlled the pattern and efficacy of the interstitial migration of leukocytes in vivo. In response to inflammatory mediators, pericytes upregulated expression of the adhesion molecule ICAM-1 and released the chemoattractant MIF. Arteriolar and capillary pericytes attracted and interacted with myeloid leukocytes after extravasating from postcapillary venules, 'instructing' them with pattern-recognition and motility programs. Inhibition of MIF neutralized the migratory cues provided to myeloid leukocytes by NG2(+) pericytes. Hence, our results identify a previously unknown role for NG2(+) pericytes as an active component of innate immune responses, which supports the immunosurveillance and effector function of extravasated neutrophils and macrophages.

Priming anti-tumor immunity by radiotherapy: Dying tumor cell-derived DAMPs trigger endothelial cell activation and recruitment of myeloid cells

“…27 Similar patterns of endothelial cell and/or pericyte activation have been reported in the field of sterile inflammation with models of laser injury and hot needle injury. 42–44 Obviously, the forms of necrotic cell death which are induced by single high dose irradiation, laser injury and hot needle injury as well as the repertoire of released DAMPs share similarities, irrespective if the dying cells are malignant or not. This is further underlined by the dynamics of myeloid cell recruitment: Initially, neutrophils are recruited followed by monocytic cells in a second wave.…”

Lung Pericytes and Resident Fibroblasts

“…Another investigation found that factors from NG2 þ pericytes attracted monocytes as well as neutrophils, and also altered the subsequent migration and responsiveness of these passing inflammatory leukocytes after they moved into the interstitial tissue. 23 Expression profiling revealed that the chemotaxis pathway was more active in FoxD1 þ /Col1 À pericytes than in other lung fibroblasts, including higher levels of Ccl4 (macrophage inflammatory protein-1b), Cxcl2 (macrophage inflammatory protein-2), Ccl21 (secondary lymphoid-tissue chemokine), and Ccl5 (regulated on activation normal T cell expressed and secreted), which combined could attract neutrophils, monocytes, macrophages, dendritic cells, NK cells, and other classes of innate lymphocytes, and T cells (Figure 3). 10,63 The Col1 À pericyte subset also preferentially expressed a variety of immune sensing and response genes.…”

“…6,53,58,64,68 Indeed, most of the immunological genes and functions identified in pericytes were long since recognized and still most commonly studied in monocytes and macrophages. 10,23,53,58,62 Distinctions between resident tissue macrophages and macrophages differentiating from immigrating monocytes have recently become far better appreciated. Resident tissue macrophages have unexpectedly but commonly been found to react with low sensitivity to signals from microbes or damage, and to respond without producing high levels of proinflammatory and profibrotic cytokines.…”

Pericytes, mesenchymal stem cells and their contributions to tissue repair

“…Pericytes have also been shown to play a role in the innate immune response by controlling leukocyte trafficking to inflamed tissue (Stark et al, 2013). Following the induction of sterile inflammation, NG2+ pericytes have been shown to express ICAM-1, allowing engagement with monocytes and neutrophils, and to secrete chemoattractants such as MIF (macrophage migrationinhibitory factor).…”

“…Following the induction of sterile inflammation, NG2+ pericytes have been shown to express ICAM-1, allowing engagement with monocytes and neutrophils, and to secrete chemoattractants such as MIF (macrophage migrationinhibitory factor). The resulting change triggers the migration of neutrophils and macrophages from postcapillary venules mediated by ICAM-1 and MIF (Stark et al, 2013). Using 4D real-time microscopy, Proebstl et al observed that pericytes actively support neutrophil migration by changes in morphology allowing for larger gaps whereby neutrophils enter into the circulation (Proebstl et al, 2012).…”