CCL19-CCR7–dependent reverse transendothelial migration of myeloid cells clears Chlamydia muridarum from the arterial intima

Abstract

Regions of the normal arterial intima predisposed to atherosclerosis are sites of ongoing monocyte trafficking and also contain resident myeloid cells with features of dendritic cells. However, the pathophysiological roles of these cells are poorly understood. Here we found that intimal myeloid cells underwent reverse transendothelial migration (RTM) into the arterial circulation after systemic stimulation of pattern-recognition receptors (PRRs). This process was dependent on expression of the chemokine receptor CCR7 and its ligand CCL19 by intimal myeloid cells. In mice infected with the intracellular pathogen Chlamydia muridarum, blood monocytes disseminated infection to the intima. Subsequent CCL19-CCR7-dependent RTM was critical for the clearance of intimal C. muridarum. This process was inhibited by hypercholesterolemia. Thus, RTM protects the normal arterial intima, and compromised RTM during atherogenesis might contribute to the intracellular retention of pathogens in atherosclerotic lesions.

Amelioration of colitis through blocking lymphocytes entry to Peyer's patches by sphingosine‐1‐phosphate lyase inhibitor

“…In this study, we evaluated the effects of modification of S1P by an SPL inhibitor, THI on PPs. S1P has been reported to function at many points of lymphocyte migration, possibly by forming an S1P gradient in the stroma, modifying the endothelial tight junctions, or controlling reverse TEM via cooperation with chemokine receptors . For the first time, we showed that THI almost blocked the entrance of lymphocytes through the endothelium by using a CLSM, compatible with FCM analysis showing reduced ratio of naïve T lymphocytes in TDLs.…”

“…S1P has been reported to function at many points of lymphocyte migration, possibly by forming an S1P gradient in the stroma, 13 modifying the endothelial tight junctions, 14 or controlling reverse TEM via cooperation with chemokine receptors. 15 For the first time, we showed that THI almost blocked the entrance of lymphocytes through the endothelium by using a CLSM, compatible with FCM analysis showing reduced ratio of naïve T lymphocytes in TDLs. In addition to the reduction by THI of circulating and colonic infiltrating lymphocytes, our microscopic observation strongly suggested that the blockade of lymphocyte entering from HEVs by THI is firmly involved in modulation of gut immunity, possibly through modulating S1PR on HEVs, as shown in a previous report.…”

“…Recently, S1P 1 agonist Ozanimod was reported to be effective in the treatment of ulcerative colitis . In addition, S1P has been reported to exert effects at other points of lymphocyte migration possibly by forming an S1P gradient in the stroma, modifying endothelial tight junctions, and controlling reverse transendothelial migration (TEM) via cooperation with chemokine receptors . S1P has been shown to be crucial for lymphocyte migration throughout the body, but how S1P regulates lymphocyte dynamics from HEVs to LCs in the stroma of PPs has never been observed in detail.…”

Myeloid cells in cardiovascular organs

“…Because cell exit may not be a frequent event, it remains challenging to image long enough to observe such an event in the fairly small field of view of microscopic imaging systems, in particular when considering the surgically exposed heart or atherosclerotic plaque. On this note, a clever experiment recently examined the exit of dendritic cells from the mouse aorta by investigating the eluate of the isolated vessel with flow cytometry . While this in vitro wash out setup has limitations such as severance of lymphatic connections, the method is able to enumerate relatively rare events.…”

Readapting the adaptive immune response – therapeutic strategies for atherosclerosis

“…T cell responses in perivascular adipose tissue are essential for the development of experimental hypertension (Itani et al, ), although human evidence of these links is sparse. In early atherosclerosis, dendritic cells scanning sites of atherosclerosis susceptibility were recently shown to exit back into the vessel lumen (intravasation) (Roufaiel et al, ), providing another potential route and suggesting systemic T cell recruitment.…”