No abstract

Ly6C hi monocytes migrate to injured sites and induce inflammation in the acute phase of tissue injury. However, once the causes of tissue injury are eliminated, monocyte-derived macrophages contribute to the resolution of inflammation and tissue repair. It remains unclear whether the emergence of these immunoregulatory macrophages is attributed to the phenotypic conversion of inflammatory monocytes in situ or to the recruitment of bone marrowderived regulatory cells de novo. Here, we identified a subpopulation of Ly6C hi monocytes that contribute to the resolution of inflammation and tissue repair. Ym1 + Ly6C hi monocytes greatly expanded in bone marrow during the recovery phase of systemic inflammation or tissue injury. Ym1 + Ly6C hi monocytes infiltrating into an injured site exhibited immunoregulatory and tissue-reparative phenotypes. Deletion of Ym1 + Ly6C hi monocytes resulted in delayed recovery from colitis. These results demonstrate that a distinct monocyte subpopulation destined to act in immunoregulation is generated in bone marrow and participates in resolution of inflammation and tissue repair. Emergence of immunoregulatory Ym1 + Ly6C hi monocytes during recovery phase of tissue injury.

Tissue macrophages comprise heterogeneous subsets that differ in localization, phenotype and ontogeny. They acquire tissue-specific phenotype in order to maintain normal tissue physiology. This review summarizes the current knowledge about the functions of CD169-positive macrophage subset residing in the lymphoid organs and intestinal tract. Strategically positioned at the interface between tissue and circulating fluid, CD169+ macrophages in the lymphoid organs capture blood- and lymph-borne particulate materials. Antigen information relayed by CD169+ macrophages to neighbouring immune cells is important for enhancement of antimicrobial and antitumour immunity as well as induction of tolerance. In the intestinal tract, CD169+ macrophages localize distantly from epithelial border. Following mucosal injury, they exacerbate inflammation by producing CCL8 that recruits inflammatory monocytes. As such, a better understanding of CD169+ macrophage phenotypes may enable the design of tissue-specific therapies for both immunological and non-immunological diseases.

Macrophages manifest distinct phenotype according to the organs in which they reside. In addition, they flexibly switch their character in adaptation to the changing environment. However, the molecular basis that explains the conversion of the macrophage phenotype has so far been unexplored. We find that CD169 macrophages change their phenotype by regulating the level of a transcription factor Maf both in vitro and in vivo in C57BL/6J mice. When CD169 macrophages were exposed to bacterial components, they expressed an array of acute inflammatory response genes in Maf-dependent manner and simultaneously start to downregulate Maf. This Maf suppression is dependent on accelerated degradation through proteasome pathway and microRNA-mediated silencing. The downregulation of Maf unlocks the NF-E2-related factor 2-dominant, cytoprotective/antioxidative program in the same macrophages. The present study provides new insights into the previously unanswered question of how macrophages initiate proinflammatory responses while retaining their capacity to repair injured tissues during inflammation.

In order to support bone marrow regeneration after myeloablation, hematopoietic stem cells (HSCs) actively divide to provide both stem and progenitor cells. However, the mechanisms regulating HSC function and cell fate choice during hematopoietic recovery remain unclear. We herein provide novel insights into HSC regulation during regeneration by focusing on mitochondrial metabolism and ATP citrate lyase (ACLY). After 5-fluorouracilinduced myeloablation, HSCs highly expressing endothelial protein C receptor (EPCR high ) were enriched within the stem cell fraction at the expense of more proliferative EPCR Low HSCs. These EPCR High HSCs were initially more primitive than EPCR Low HSCs and enabled stem cell expansion by enhancing histone acetylation, due to increased activity of ACLY in the early phase of hematopoietic regeneration. In the late phase of recovery, HSCs enhanced differentiation potential by increasing the accessibility of cis-regulatory elements in progenitor cell-related genes, such as CD48. In conditions of reduced mitochondrial metabolism and ACLY activity, these HSCs maintained stem cell phenotypes, while ACLYdependent histone acetylation promoted differentiation into CD48 + progenitor cells. Collectively, these results indicate that the dynamic control of ACLY-dependent metabolism and epigenetic alterations is essential for HSC regulation during hematopoietic regeneration.

Systemic and local inflammation associated with therapeutic intervention of primary tumor occasionally promotes metastatic recurrence in mouse and human. However, it remains unclear what types of immune cells are involved in this process. Here, we found that the tissue-repair-promoting Ym1+Ly6Chi monocyte subset expanded as a result of systemic and local inflammation induced by intravenous injection of lipopolysaccharide or resection of primary tumor and promoted lung metastasis originating from circulating tumor cells (CTCs). Deletion of this subset suppressed metastasis induced by the inflammation. Furthermore, transfer of Ym1+Ly6Chi monocytes into naïve mice promoted lung metastasis in the mice. Ym1+Ly6Chi monocytes highly expressed matrix metalloproteinase-9 (MMP-9) and CXCR4. MMP-9 inhibitor and CXCR4 antagonist decreased Ym1+Ly6Chi-monocyte-promoted lung metastasis. These findings indicate that Ym1+Ly6Chi monocytes are therapeutic target cells for metastasis originating from CTCs associated with systemic and local inflammation. In addition, these findings provide a novel predictive cellular biomarker for metastatic recurrence after intervention for primary tumor.

Our findings first suggest that the association between HSPA1B-179C>T and 1267A>G gene sequence variations might be implicated in the development of AERD.

Highlights d Specific bivalent gene body signature regulates VEGFresponsive angiogenic acute TFs d Non-canonical PRC1.3 transiently transactivates PRC2enriched angiogenic genes d VEGF-NFAT-associated epigenome modifier PTIP directs NFAT-targeted gene activation d Reductions in PRC1.3 or PTIP lead to impaired postnatal angiogenesis