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Metabolic influence on macrophage polarization and pathogenesis
( Bikash Thapa ),( Keunwook Lee ) 생화학분자생물학회(구 한국생화학분자생물학회) 2019 BMB Reports Vol.52 No.6
Macrophages play an essential role not only in mediating the first line of defense but also in maintaining tissue homeostasis. In response to extrinsic factors derived from a given tissue, macrophages activate different functional programs to produce polarized macrophage populations responsible for inducing inflammation against microbes, removing cellular debris, and tissue repair. However, accumulating evidence has revealed that macrophage polarization is pivotal in the pathophysiology of metabolic syndromes and cancer, as well as in infectious and autoimmune diseases. Recent advances in transcriptomic and metabolomic studies have highlighted the link between metabolic rewiring of macrophages and their functional plasticity. These findings imply that metabolic adaption to their surrounding microenvironment instructs activation of macrophages with functionally distinct phenotypes, which in turn probably leads to the pathogenesis of a wide spectrum of diseases. In this review, we have introduced emerging concepts in immunometabolism with focus on the impact on functional activation of macrophages. Furthermore, we have discussed the implication of macrophage plasticity on the pathogenesis of metabolic syndromes and cancer, and how the disease microenvironment manipulates macrophage metabolism with regard to the pathophysiology. [BMB Reports 2019; 52(6): 360-372]
Bikash Thapa,Dong-Gyu Kim,Seongwon Pak,Dohyeon Chung,Jungwoo Shin,Keunwook Lee 한국실험동물학회 2021 한국실험동물학회 학술발표대회 논문집 Vol.2021 No.7
Activated B cells in the germinal center (GC) undergo clonal expansion along with immunoglobulin isotype switching and affinity maturation, leading to differentiation into plasma cells that produce appropriate humoral immunity against invading pathogen. Although PI3K/mTOR signaling is indispensable for survival and proliferation of B cells, little is known about how this signaling pathway integrates environmental milieu within the GCs to regulate GC reactions and to yield plasma cells. In this study, we dissected the impact of PI3K/mTOR signaling pathway on antibody responses by combination of the inducible deletion of Pten (a PI3K-antagonistic lipid phosphatase), Raptor (a subunit of mTORC1), and Rictor (a subunit of mTORC2). Rag2-/- mice were reconstituted with naïve B cells isolated from the inducible KO mice along with normal CD4 T cells and then immunized with NP-ovalbumin. Mice that received Pten depleted B cells exhibited impaired class switching to IgG1 and production of high affinity antibodies against the NP antigen in the sera. On the other hand, inactivation of mTORC2 by depleting Rictor under Pten loss in B cells rescued IgG1 class switching and affinity maturation of NP-specific antibodies whereas that of mTORC1 by depletion Raptor did not. To delineate the mechanism, we adapted a co-culture system to generate GC B cells and plasmablasts (PBs) ex vivo. B cells depleted Pten differentiated into PBs expressing predominantly IgM and less IgG1 in the co-cultivation which was comparable to the control PBs. Finally, we performed transcriptomic analysis of PB cells and mapped to the set of B cell function-associated genes under the regulation of the PI3K-PTEN-mTORC2 signaling network. It is in progress to determine whether this signaling modulation within B cell compartment is required for protective antibody responses against influenza virus. Collectively, out data provide a mechanistic insight by which PTEN and mTORC2 tune up the PI3K signaling pathway to promote class-switching and affinity maturation of antibodies during GC reaction.
( Bikash Thapa ),( Seongwon Pak ),( Hyun-joo Kwon ),( Keunwook Lee ) 한국응용약물학회 2019 Biomolecules & Therapeutics(구 응용약물학회지) Vol.27 No.5
Angelica gigas has been used as a Korean traditional medicine for pain relief and gynecological health. Although the extracts are reported to have an anti-inflammatory property, the bioactive compounds of the herbal plant and the effect on T cell responses are unclear. In this study, we identified decursinol angelate (DA) as an immunomodulatory ingredient of A. gigas and demonstrated its suppressive effect on type 17 helper T (Th17) cell responses. Helper T cell culture experiments revealed that DA impeded the differentiation of Th17 cells and IL-17 production without affecting the survival and proliferation of CD4 T cells. By using a dextran sodium sulfate (DSS)-induced colitis model, we determined the therapeutic potential of DA for the treatment of ulcerative colitis. DA treatment attenuated the severity of colitis including a reduction in weight loss, colon shortening, and protection from colonic tissue damage induced by DSS administration. Intriguingly, Th17 cells concurrently with neutrophils in the colitis tissues were significantly decreased by the DA treatment. Overall, our experimental evidence reveals for the first time that DA is an anti-inflammatory compound to modulate inflammatory T cells, and suggests DA as a potential therapeutic agent to manage inflammatory conditions associated with Th17 cell responses.