CCR2 Deficiency Impairs Ly6C(lo) and Ly6C(hi) Monocyte Responses in Orientia tsutsugamushi Infection.

Orientia (O.) tsutsugamushi, the causative agent of scrub typhus, is a neglected, obligate intracellular bacterium that has a prominent tropism for monocytes and macrophages. Complications often involve the lung, where interstitial pneumonia is a typical finding. The severity of scrub typhus in humans has been linked to altered plasma concentrations of chemokines which are known to act as chemoattractants for myeloid cells. The trafficking and function of monocyte responses is critically regulated by interaction of the CC chemokine ligand 2 (CCL2) and its CC chemokine receptor CCR2. In a self-healing mouse model of intradermal infection with the human-pathogenic Karp strain of O. tsutsugamushi, we investigated the role of CCR2 on bacterial dissemination, development of symptoms, lung histology and monocyte subsets in blood and lungs. CCR2-deficient mice showed a delayed onset of disease and resolution of symptoms, higher concentrations and impaired clearance of bacteria in the lung and the liver, accompanied by a slow infiltration of interstitial macrophages into the lungs. In the blood, we found an induction of circulating monocytes that depended on CCR2, while only a small increase in Ly6Chi monocytes was observed in CCR2-/- mice. In the lung, significantly higher numbers of Ly6Chi and Ly6Clo monocytes were found in the C57BL/6 mice compared to CCR2-/- mice. Both wildtype and CCR2-deficient mice developed an inflammatory milieu as shown by cytokine and inos/arg1 mRNA induction in the lung, but with delayed kinetics in CCR2-deficient mice. Histopathology revealed that infiltration of macrophages to the parenchyma, but not into the peribronchial tissue, depended on CCR2. In sum, our data suggest that in Orientia infection, CCR2 drives blood monocytosis and the influx and activation of Ly6Chi and Ly6Clo monocytes into the lung, thereby accelerating bacterial replication and development of interstitial pulmonary inflammation.

Petermann M ，Orfanos Z ，Sellau J ，Gharaibeh M ，Lotter H ，Fleischer B ，Keller C ... -  《Frontiers in Immunology》

Orientia tsutsugamushi stimulates an original gene expression program in monocytes: relationship with gene expression in patients with scrub typhus.

Tantibhedhyangkul W ，Prachason T ，Waywa D ，El Filali A ，Ghigo E ，Thongnoppakhun W ，Raoult D ，Suputtamongkol Y ，Capo C ，Limwongse C ，Mege JL ... -  《PLoS Neglected Tropical Diseases》

Ly6C(high) Monocytes Oscillate in the Heart During Homeostasis and After Myocardial Infarction-Brief Report.

Circadian regulation of neutrophil homeostasis affects myocardial infarction (MI) healing. It is unknown whether diurnal variations of monocyte counts exist in the heart and whether this affects their cardiac infiltration in response to MI. Murine blood and organs were harvested at distinct times of day and analyzed by flow cytometry. Ly6Chigh monocyte surface expression levels of chemokine receptors (CCR) were ≈2-fold higher at the beginning of the active phase, Zeitgeber Time (ZT) 13 compared with ZT5. This was because of enhanced receptor surface expression at ZT13, whereas no significant changes in total cellular protein levels were found. Most blood Ly6Chigh monocytes were CCR2high, whereas only a minority was CCR1high and CCR5high. We also found diurnal changes of classical monocyte blood counts in humans, being higher in the evening, while exhibiting enhanced CCR2 surface expression in the morning. In support of monocyte oscillations between blood and tissue, murine cardiac Ly6Chigh monocyte counts were highest at ZT13, accompanied by an upregulation of cardiac CC chemokine ligand 2 mRNA. Mice subjected to MI at ZT13 had an even higher upregulation of CCR2 surface expression on circulating monocytes compared with noninfarcted mice and more elevated cardiac CC chemokine ligand 2 protein expression and more pronounced Ly6Chigh monocyte infiltration compared with ZT5-infarcted mice. Concomitantly, CCR2 antagonism only inhibited the excessive cardiac Ly6Chigh monocyte infiltration after ZT13 MI but not ZT5 MI. CCR2 surface expression on Ly6Chigh monocytes changes in a time-of-day-dependent manner, which crucially affects cardiac monocyte recruitment after an acute ischemic event.

Schloss MJ ，Hilby M ，Nitz K ，Guillamat Prats R ，Ferraro B ，Leoni G ，Soehnlein O ，Kessler T ，He W ，Luckow B ，Horckmans M ，Weber C ，Duchene J ，Steffens S ... -  《-》

Spatio-temporal profile, phenotypic diversity, and fate of recruited monocytes into the post-ischemic brain.

Garcia-Bonilla L ，Faraco G ，Moore J ，Murphy M ，Racchumi G ，Srinivasan J ，Brea D ，Iadecola C ，Anrather J ... -  《Journal of Neuroinflammation》

Dissemination of Orientia tsutsugamushi and inflammatory responses in a murine model of scrub typhus.

Keller CA ，Hauptmann M ，Kolbaum J ，Gharaibeh M ，Neumann M ，Glatzel M ，Fleischer B ... -  《PLoS Neglected Tropical Diseases》