C-C Chemokine Receptor 7 (CCR7) mediates T-cell acute lymphoblastic leukemia (T-ALL) invasion of the central nervous system (CNS) mediated by chemotactic migration to C-C chemokine ligand 19 (CCL19). To determine if a CCL19 antagonist, CCL198-83, could inhibit CCR7-induced chemotaxis and signaling via CCL19 but not CCL21, we used transwell migration and Ca2+ mobilization signaling assays. We found that in response to CCL19, human T-ALL cells employ β2 integrins to invade human brain microvascular endothelial cell monolayers. In vivo, using an inducible mouse model of T-ALL, we found that we were able to increase the survival of the mice treated with CCL198-83 when compared to non-treated controls. Overall, our results describe a targetable cell surface receptor, CCR7, which can be inhibited to prevent β2-integrin-mediated T-ALL invasion of the CNS and potentially provides a platform for the pharmacological inhibition of T-ALL cell entry into the CNS.

Terminally differentiated keratinocytes are critical for epidermal function and are surrounded by involucrin (IVL). Increased IVL expression is associated with a near-selective sweep in European populations compared with those in Africa. This positive selection for increased IVL in the epidermis identifies human adaptation outside of Africa. The functional significance is unclear. We hypothesize that IVL modulates the environmentally sensitive vitamin D receptor (VDR) in the epidermis. We investigated VDR activity in Ivl‒/‒ and wild-type mice using vitamin D agonist (MC903) treatment and comprehensively determined the inflammatory response using single-cell RNA sequencing and associated skin microbiome changes using 16S bacterial phylotyping. VDR activity and target gene expression were reduced in Ivl‒/‒ mouse skin, with decreased MC903-mediated skin inflammation and significant reductions in CD4+ T cells, basophils, macrophages, monocytes, and type II basal keratinocytes and an increase in suprabasal keratinocytes. Coinciding with the dampened MC903-mediated inflammation, the skin microbiota of Ivl‒/‒ mice was more stable than that of the wild-type mice, which exhibited an MC903-responsive increase in Bacteroidetes and a decrease in Firmicutes. Together, our studies in Ivl‒/‒ mice identify a functional role for IVL to positively impact VDR activity and suggest an emerging IVL/VDR paradigm for adaptation in the human epidermis.
Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.

During aging, mitochondrial DNA (mtDNA) can accumulate mutations leading to increasing levels of reactive oxygen species (ROS). Increased ROS were described to activate formerly quiescent hematopoietic stem cells (HSC). Mutations in mtDNA were shown to enhance the risk for myelodysplastic syndrome and leukemia. However, the complex relationship between mtDNA variations, ROS and aging of the hematopoietic system is not fully understood.Herein, three mouse strains with mtDNA polymorphisms in genes of respiratory chain complexes I (ND4), III (CYTB) and IV (COX3) were compared to a reference strain during aging. Analysis focused on ROS and ATP levels, bone marrow composition and blood counts. Additionally, hematopoietic restoration capacity following cytotoxic stress was tested.Mice with polymorphisms in ND4 and CYTB gene had significantly decreasing ROS levels in bone marrow cells during aging, without effecting ATP levels. In addition, the frequency of stem and progenitor cells increased during aging but the amount of lymphocytes in the peripheral blood decreased during aging.In summary, the presence of mtDNA polymorphisms affecting the respiratory chain complexes I, III and IV was associated with altered ROS levels as well as changes in BM and peripheral blood composition during aging.

Mitochondrial DNA (mtDNA) encodes for the respiratory chain proteins. Genetic alterations in mtDNA have been described during aging and linked to impaired hematopoiesis.
We investigated two novel conplastic mouse strains harboring a mitochondrial nt7778 G/T polymorphism leading to an amino acid exchange in respiratory chain complex V. Effects on reactive oxygen species (ROS) and adenosine triphosphate (ATP) levels, as well as bone marrow composition and peripheral blood counts, were investigated during aging (up to 24 month).
The polymorphism correlated with significantly decreased ROS levels in aged mice. Effects on hematopoiesis were marginal and not statistically significant: numbers of erythroid cells in bone marrow, as well as mean corpuscular hemoglobin, tended to decrease over time.
The investigated polymorphism is associated with decreased ROS levels in aged hematopoietic cells but does not significantly influence hematopoiesis itself.
Copyright © 2016 International Institute of Anticancer Research (Dr. John G. Delinassios), All rights reserved.

Antibodies are critical for defense against a variety of microbes, but they may also be pathogenic in some autoimmune diseases. Many effector functions of antibodies are mediated by Fcγ receptors (FcγRs), which are found on most immune cells, including dendritic cells (DCs)-important antigen-presenting cells that play a central role in inducing antigen-specific tolerance or immunity. Following antigen acquisition in peripheral tissues, DCs migrate to draining lymph nodes via the lymphatics to present antigen to T cells. Here we demonstrate that FcγR engagement by IgG immune complexes (ICs) stimulates DC migration from peripheral tissues to the paracortex of draining lymph nodes. In vitro, IC-stimulated mouse and human DCs showed greater directional migration in a chemokine (C-C) ligand 19 (CCL19) gradient and increased chemokine (C-C) receptor 7 (CCR7) expression. Using intravital two-photon microscopy, we observed that local administration of IC resulted in dermal DC mobilization. We confirmed that dermal DC migration to lymph nodes depended on CCR7 and increased in the absence of the inhibitory receptor FcγRIIB. These observations have relevance to autoimmunity because autoantibody-containing serum from humans with systemic lupus erythematosus (SLE) and from a mouse model of SLE also increased dermal DC migration in vivo, suggesting that this process may occur in lupus, potentially driving the inappropriate localization of autoantigen-bearing DCs.