PMC:5767236 / 12559-15656 JSONTXT

{"project":"MyTest","denotations":[{"id":"29375564-20856220-34933844","span":{"begin":395,"end":397},"obj":"20856220"},{"id":"29375564-22378047-34933845","span":{"begin":399,"end":401},"obj":"22378047"},{"id":"29375564-20219869-34933846","span":{"begin":1172,"end":1174},"obj":"20219869"},{"id":"29375564-22144566-34933847","span":{"begin":1691,"end":1692},"obj":"22144566"},{"id":"29375564-17485518-34933848","span":{"begin":1935,"end":1937},"obj":"17485518"},{"id":"29375564-23434060-34933848","span":{"begin":1935,"end":1937},"obj":"23434060"},{"id":"29375564-23100531-34933848","span":{"begin":1935,"end":1937},"obj":"23100531"},{"id":"29375564-23743228-34933849","span":{"begin":2036,"end":2038},"obj":"23743228"},{"id":"29375564-25700973-34933850","span":{"begin":2370,"end":2372},"obj":"25700973"},{"id":"29375564-21566158-34933851","span":{"begin":2864,"end":2866},"obj":"21566158"},{"id":"29375564-24101381-34933852","span":{"begin":2868,"end":2870},"obj":"24101381"},{"id":"29375564-27592711-34933853","span":{"begin":2976,"end":2978},"obj":"27592711"}],"namespaces":[{"prefix":"_base","uri":"https://www.uniprot.org/uniprot/testbase"},{"prefix":"UniProtKB","uri":"https://www.uniprot.org/uniprot/"},{"prefix":"uniprot","uri":"https://www.uniprot.org/uniprotkb/"}],"text":"Phenotypes and Functions of Macrophages\nSeveral studies on macrophage biology have focused on the particular functions that these cells acquire after tissue accumulation. Macrophages are highly plastic and can adapt to environmental stimuli, displaying either a classically activated (M1) or alternatively activated (M2) profile, which represent extremes of a spectrum of functional phenotypes (25, 26). M1 macrophages are activated by pro-inflammatory Th1 cytokines and LPS. Besides being antigen-presenting cells, the M1 subset shows an enhanced microbicidal capacity attributable to the production of reactive oxygen species (ROS) (such as hydrogen peroxide, superoxide, nitric oxide (NO), and peroxynitrite) and inflammatory cytokines (TNF, IL-1β, IL-12, and IL-23). On the other extreme, M2 macrophages are activated by Th2 cytokines (IL-4 and IL-13) or by anti-inflammatory mediators (IL-10), enhancing the arginase activity and mannose receptor (CD206) expression, to promote wound healing and reduce Th1 response. However, the M2 subset development can also be detrimental to host tissue, leading to fibrosis when their matrix-enhancing activity is not regulated (27). Although embryonic and monocyte-derived macrophages likely are on a continuum spectrum that lies between (and outside of) the M1 and M2 classifications, the terminology nevertheless has been helpful in order to elucidate macrophage heterogeneity. When Ly6Chigh monocytes are recruited to atherosclerotic lesions, they mature to F4/80+ macrophages. In a persistent inflammatory environment, these Ly6Chigh monocyte-derived macrophages contribute to oxidative stress and are inflammatory by producing IL-1β and TNF (9). In this respect, Ly6Chigh monocyte-derived cells are M1 macrophages. In the setting of inflammation resolution, M1 macrophages are replaced by M2 repairing macrophages. Although it has been proposed that M1 to M2 conversion occurs locally (28–30), M2 macrophages also could derive from non-classical and less inflammatory Ly6Clow monocytes (12). Otherwise, M2 macrophages may arise through direct differentiation of Ly6Chigh monocytes in a microenvironment that favors wound healing. This option should be further explored because it is enticing for potential therapeutic reasons.\nCardiac resident macrophages coexpress M1 and M2 markers suggesting no specific polarization (31). However, within myocardium macrophages respond to systemic Th2 environment induced by helminth parasites infection, adopting an M2 phenotype associated with enhanced fibrosis. In this model, the increased amount of cardiac macrophages relies on recruitment of Ly6ChighCCR2+ monocytes instead of IL-4-induced expansion. In this sense, Jenkins et al. have shown that IL-4 and IL-13 through IL-4Rα not only activate macrophages but also cause proliferative expansion of resident macrophages (32, 33). Moreover, IL-33 also induces macrophages proliferation, but in an IL-4Rα-signaling-independent manner (34), suggesting that the number and activation state of cardiac macrophages largely depend on mediators locally produced."}

{"project":"TEST0","denotations":[{"id":"29375564-224-230-3353188","span":{"begin":395,"end":397},"obj":"[\"20856220\"]"},{"id":"29375564-228-234-3353189","span":{"begin":399,"end":401},"obj":"[\"22378047\"]"},{"id":"29375564-150-156-3353190","span":{"begin":1172,"end":1174},"obj":"[\"20219869\"]"},{"id":"29375564-166-171-3353191","span":{"begin":1691,"end":1692},"obj":"[\"22144566\"]"},{"id":"29375564-71-77-3353192","span":{"begin":1935,"end":1937},"obj":"[\"17485518\", \"23434060\", \"23100531\"]"},{"id":"29375564-172-178-3353193","span":{"begin":2036,"end":2038},"obj":"[\"23743228\"]"},{"id":"29375564-94-100-3353194","span":{"begin":2370,"end":2372},"obj":"[\"25700973\"]"},{"id":"29375564-170-176-3353195","span":{"begin":2864,"end":2866},"obj":"[\"21566158\"]"},{"id":"29375564-174-180-3353196","span":{"begin":2868,"end":2870},"obj":"[\"24101381\"]"},{"id":"29375564-103-109-3353197","span":{"begin":2976,"end":2978},"obj":"[\"27592711\"]"}],"text":"Phenotypes and Functions of Macrophages\nSeveral studies on macrophage biology have focused on the particular functions that these cells acquire after tissue accumulation. Macrophages are highly plastic and can adapt to environmental stimuli, displaying either a classically activated (M1) or alternatively activated (M2) profile, which represent extremes of a spectrum of functional phenotypes (25, 26). M1 macrophages are activated by pro-inflammatory Th1 cytokines and LPS. Besides being antigen-presenting cells, the M1 subset shows an enhanced microbicidal capacity attributable to the production of reactive oxygen species (ROS) (such as hydrogen peroxide, superoxide, nitric oxide (NO), and peroxynitrite) and inflammatory cytokines (TNF, IL-1β, IL-12, and IL-23). On the other extreme, M2 macrophages are activated by Th2 cytokines (IL-4 and IL-13) or by anti-inflammatory mediators (IL-10), enhancing the arginase activity and mannose receptor (CD206) expression, to promote wound healing and reduce Th1 response. However, the M2 subset development can also be detrimental to host tissue, leading to fibrosis when their matrix-enhancing activity is not regulated (27). Although embryonic and monocyte-derived macrophages likely are on a continuum spectrum that lies between (and outside of) the M1 and M2 classifications, the terminology nevertheless has been helpful in order to elucidate macrophage heterogeneity. When Ly6Chigh monocytes are recruited to atherosclerotic lesions, they mature to F4/80+ macrophages. In a persistent inflammatory environment, these Ly6Chigh monocyte-derived macrophages contribute to oxidative stress and are inflammatory by producing IL-1β and TNF (9). In this respect, Ly6Chigh monocyte-derived cells are M1 macrophages. In the setting of inflammation resolution, M1 macrophages are replaced by M2 repairing macrophages. Although it has been proposed that M1 to M2 conversion occurs locally (28–30), M2 macrophages also could derive from non-classical and less inflammatory Ly6Clow monocytes (12). Otherwise, M2 macrophages may arise through direct differentiation of Ly6Chigh monocytes in a microenvironment that favors wound healing. This option should be further explored because it is enticing for potential therapeutic reasons.\nCardiac resident macrophages coexpress M1 and M2 markers suggesting no specific polarization (31). However, within myocardium macrophages respond to systemic Th2 environment induced by helminth parasites infection, adopting an M2 phenotype associated with enhanced fibrosis. In this model, the increased amount of cardiac macrophages relies on recruitment of Ly6ChighCCR2+ monocytes instead of IL-4-induced expansion. In this sense, Jenkins et al. have shown that IL-4 and IL-13 through IL-4Rα not only activate macrophages but also cause proliferative expansion of resident macrophages (32, 33). Moreover, IL-33 also induces macrophages proliferation, but in an IL-4Rα-signaling-independent manner (34), suggesting that the number and activation state of cardiac macrophages largely depend on mediators locally produced."}

{"project":"2_test","denotations":[{"id":"29375564-20856220-34933844","span":{"begin":395,"end":397},"obj":"20856220"},{"id":"29375564-22378047-34933845","span":{"begin":399,"end":401},"obj":"22378047"},{"id":"29375564-20219869-34933846","span":{"begin":1172,"end":1174},"obj":"20219869"},{"id":"29375564-22144566-34933847","span":{"begin":1691,"end":1692},"obj":"22144566"},{"id":"29375564-17485518-34933848","span":{"begin":1935,"end":1937},"obj":"17485518"},{"id":"29375564-23434060-34933848","span":{"begin":1935,"end":1937},"obj":"23434060"},{"id":"29375564-23100531-34933848","span":{"begin":1935,"end":1937},"obj":"23100531"},{"id":"29375564-23743228-34933849","span":{"begin":2036,"end":2038},"obj":"23743228"},{"id":"29375564-25700973-34933850","span":{"begin":2370,"end":2372},"obj":"25700973"},{"id":"29375564-21566158-34933851","span":{"begin":2864,"end":2866},"obj":"21566158"},{"id":"29375564-24101381-34933852","span":{"begin":2868,"end":2870},"obj":"24101381"},{"id":"29375564-27592711-34933853","span":{"begin":2976,"end":2978},"obj":"27592711"}],"text":"Phenotypes and Functions of Macrophages\nSeveral studies on macrophage biology have focused on the particular functions that these cells acquire after tissue accumulation. Macrophages are highly plastic and can adapt to environmental stimuli, displaying either a classically activated (M1) or alternatively activated (M2) profile, which represent extremes of a spectrum of functional phenotypes (25, 26). M1 macrophages are activated by pro-inflammatory Th1 cytokines and LPS. Besides being antigen-presenting cells, the M1 subset shows an enhanced microbicidal capacity attributable to the production of reactive oxygen species (ROS) (such as hydrogen peroxide, superoxide, nitric oxide (NO), and peroxynitrite) and inflammatory cytokines (TNF, IL-1β, IL-12, and IL-23). On the other extreme, M2 macrophages are activated by Th2 cytokines (IL-4 and IL-13) or by anti-inflammatory mediators (IL-10), enhancing the arginase activity and mannose receptor (CD206) expression, to promote wound healing and reduce Th1 response. However, the M2 subset development can also be detrimental to host tissue, leading to fibrosis when their matrix-enhancing activity is not regulated (27). Although embryonic and monocyte-derived macrophages likely are on a continuum spectrum that lies between (and outside of) the M1 and M2 classifications, the terminology nevertheless has been helpful in order to elucidate macrophage heterogeneity. When Ly6Chigh monocytes are recruited to atherosclerotic lesions, they mature to F4/80+ macrophages. In a persistent inflammatory environment, these Ly6Chigh monocyte-derived macrophages contribute to oxidative stress and are inflammatory by producing IL-1β and TNF (9). In this respect, Ly6Chigh monocyte-derived cells are M1 macrophages. In the setting of inflammation resolution, M1 macrophages are replaced by M2 repairing macrophages. Although it has been proposed that M1 to M2 conversion occurs locally (28–30), M2 macrophages also could derive from non-classical and less inflammatory Ly6Clow monocytes (12). Otherwise, M2 macrophages may arise through direct differentiation of Ly6Chigh monocytes in a microenvironment that favors wound healing. This option should be further explored because it is enticing for potential therapeutic reasons.\nCardiac resident macrophages coexpress M1 and M2 markers suggesting no specific polarization (31). However, within myocardium macrophages respond to systemic Th2 environment induced by helminth parasites infection, adopting an M2 phenotype associated with enhanced fibrosis. In this model, the increased amount of cardiac macrophages relies on recruitment of Ly6ChighCCR2+ monocytes instead of IL-4-induced expansion. In this sense, Jenkins et al. have shown that IL-4 and IL-13 through IL-4Rα not only activate macrophages but also cause proliferative expansion of resident macrophages (32, 33). Moreover, IL-33 also induces macrophages proliferation, but in an IL-4Rα-signaling-independent manner (34), suggesting that the number and activation state of cardiac macrophages largely depend on mediators locally produced."}