MCP-1 deficiency enhances browning of adipose tissue via increased M2 polarization
JOURNAL OF ENDOCRINOLOGY
Authors: Rajasekaran, Monisha; Sul, Ok-Joo; Choi, Eun-Kyung; Kim, Ji-Eun; Suh, Jae-Hee; Choi, Hye-Seon
Obesity is strongly associated with chronic inflammation for which adipose tissue macrophages play a critical role. The objective of this study is to identify monocyte chemoattractant protein-1 (MCP-1, CCL2) as a key player governing M1-M2 macrophage polarization polarization and energy balance. We evaluated body weight, fat mass, adipocyte size and energy expenditure as well as core body temperature of Ccl2 knockout mice compared with wild-type mice. Adipose tissues, differentiated adipocyte and bone marrow-derived macrophages were assessed by qPCR, Western blot analysis and histochemistry. MCP-1 deficiency augmented energy expenditure by promoting browning in white adipose tissue and brown adipose tissue activity via increasing the expressions of Ucp1, Prdm16, Tnfrsf9, Ppargcla, Nrf1 and Th and mitochondrial DNA copy number. MCP-1 abrogation promoted M2 polarization which is characterized by increased expression of Arg1, Chil3, Il10 and Klf4 whereas it decreased M1 polarization by decreased p65 nuclear translocation and attenuated expression of Itgax, Tnf and Nos2, leading to increased browning of adipocytes. Enhanced M2 polarization and attenuated M1 polarization in the absence of MCP-1 are independent. Collectively, our results suggest that the action of MCP-1 in macrophages modulates energy expenditure by impairing browning in adipose tissue.
CD137 Ligand Is Expressed in Primary and Secondary Lymphoid Follicles and in B-cell Lymphomas Diagnostic and Therapeutic Implications
AMERICAN JOURNAL OF SURGICAL PATHOLOGY
Authors: Zhao, Shuchun; Zhang, Haiyu; Xing, Ying; Natkunam, Yasodha
CD137 ligand (4-1BB ligand, TNFSF9, CD137L) is a member of the tumor necrosis factor family whose binding to its receptor, CD137 (4-1BB, TNFRSF9), mediates costimulatory and prosurvival signals necessary for T-cell activation and regulation of humoral immune responses. Recent studies have shown that anti-CD137 immunotherapy has promise as a treatment for solid tumors and lymphoid malignancies in preclinical models. Here, we define the tissue expression profile of CD137L, which has not been previously explored. We characterized the expression of CD137L in normal and neoplastic human hematopoietic and nonhematopoietic tissue and found that CD137L is preferentially expressed in B cells of the primary follicles, mantle zones of the secondary follicles, germinal centers, and in normal endothelial cells. Double immunofluorescence labeling in tissue sections and flow cytometry analysis further showed that CD137L is a potential new marker of memory B cells. Evaluation of over 700 human hematopoietic tumors revealed that the majority of B-cell lymphomas expressed CD137L, which include mantle cell lymphoma, follicular lymphoma, and diffuse large B-cell lymphoma. In contrast, CD137L expression was lacking in Hodgkin lymphoma and T-cell lymphoma. Our findings suggest that CD137L is a novel diagnostic marker of subtypes of non-Hodgkin B-cell lymphomas and raise the possibility that its expression on tumor cells may be directly targeted for immunomodulatory therapy for lymphoid and other malignancies.