Blocking angiotensin-converting enzyme induces potent regulatory T cells and modulates TH1- and TH17-mediated autoimmunity

Platten, Michael; Youssef, Sawsan; Hur, Eun Mi; Ho, Peggy P.; Han, May; Lanz, Tobias V.; Phillips, L Taylor; Goldstein, Matthew; Bhat, R.; Raine, Cedric S.; Sobel, Raymond A.; Steinman, Lawrence

doi:10.1073/pnas.0903958106

Cited by 285 publications

(282 citation statements)

References 33 publications

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“…Thus, it has been shown that deletion of immune cells or immune suppression therapy reduces Ang II-dependent hypertension and hypertensive end organ damage, respectively (3,4). In line with these results, recent studies have provided profound evidence that AT1 receptor inhibition directly affects immune cell function and thereby ameliorates the clinical course of experimental autoimmune encephalomyelitis (EAE) (5,6) or systemic lupus erythematosus (7,8).…”

supporting

confidence: 59%

Role of the receptor Mas in macrophage-mediated inflammation in vivo

Hammer

Yang

Friedrich

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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Recently, an alternative renin–angiotensin system pathway has been described, which involves binding of angiotensin-(1–7) to its receptor Mas. The Mas axis may counterbalance angiotensin-II–mediated proinflammatory effects, likely by affecting macrophage function. Here we investigate the role of Mas in murine models of autoimmune neuroinflammation and atherosclerosis, which both involve macrophage-driven pathomechanisms. Mas signaling affected macrophage polarization, migration, and macrophage-mediated T-cell activation. Mas deficiency exacerbated the course of experimental autoimmune encephalomyelitis and increased macrophage infiltration as well as proinflammatory gene expression in the spleen and spinal cord. Furthermore, Mas deficiency promoted atherosclerosis by affecting macrophage infiltration and migration and led to increased oxidative stress as well as impaired endothelial function in ApoE-deficient mice. In summary, we identified the Mas axis as an important factor in macrophage function during inflammation of the central nervous and vascular system in vivo. Modulating the Mas axis may constitute an interesting therapeutic target in multiple sclerosis and/or atherosclerosis.

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supporting

confidence: 59%

Role of the receptor Mas in macrophage-mediated inflammation in vivo

Hammer

Yang

Friedrich

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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“…Indeed, Kit W-sh/W-sh mice show cardiomegaly 30 and may also display spontaneous hypertension, a condition associated to Corin ablation 49 that may favor EAE development, as indicated by the recent observation that anti-hypertensive drugs suppress autoimmune response in EAE. 50 The Kit W-sh/W-sh mutation may also produce dysregulations in a series of genes included in the inverted region, whose effects in immunity are largely unknown. 30 Finally, the two c-Kit-mutated strains differ in their genetic background, and the WBB6F 1 -Kit þ / þ is characterized by higher number of peritoneal MCs and neutrophils than the C57BL/6-Kit þ / þ .…”

Section: Discussionmentioning

confidence: 99%

Exacerbated experimental autoimmune encephalomyelitis in mast-cell-deficient KitW-sh/W-sh mice

Piconese

Costanza

Musio

et al. 2011

Laboratory Investigation

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Mast cell (MC)-deficient c-Kit mutant Kit W/W-v mice are protected against experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis, suggesting a detrimental role for MCs in this disease. To further investigate the role of MCs in EAE, we took advantage of a recently characterized model of MC deficiency, Kit W-sh/W-sh . Surprisingly, we observed that myelin oligodendrocyte glycoprotein (MOG) 35-55 -induced chronic EAE was exacerbated in Kit W-sh/W-sh compared with Kit þ / þ mice. Kit W-sh/W-sh mice showed more inflammatory foci in the central nervous system (CNS) and increased T-cell response against myelin. To understand whether the discrepant results obtained in Kit W-sh/W-sh and in Kit W/W-v mice were because of the different immunization protocols, we induced EAE in these two strains with varying doses of MOG and adjuvants. Although Kit W-sh/W-sh mice exhibited exacerbated EAE under all immunization protocols, Kit W/W-v mice were protected from EAE only when immunized with high, but not low, doses of antigen and adjuvants. Kit W-sh/W-sh mice reconstituted systemically, but not in the CNS, with bone marrow-derived MCs still developed exacerbated EAE, indicating that protection from disease could be exerted by MCs mainly in the CNS, and/or by other cells possibly dysregulated in Kit W-sh/W-sh mice. In summary, these data suggest to reconsider MC contribution to EAE, taking into account the variables of using different experimental models and immunization protocols. MCs are key factors in IgE-associated immediate hypersensitivity reactions, during which they release a wide spectrum of inflammatory mediators in response to IgE and antigen (Ag) stimulation. 1 However, recent findings have pointed out that MCs may exert also important effector and/or immunomodulatory functions in other physiopathological conditions as venom detoxification, pathogen clearance, tumor growth, contact hypersensitivity, allograft acceptance and autoimmunity. 2 Most of these studies have assessed the in vivo role of MCs by the use of mouse models carrying spontaneous mutations in c-Kit receptor (WBB6F 1 -Kit W/W-v or C57BL/6-Kit W-sh/W-sh mice) or c-Kit ligand (WCB6F 1 -Kitl Sl /Kitl Sl-d ), which show severe deficiency of MC populations. 3,4 MCs may either enhance or suppress the inflammation associated to different types of autoimmune diseases. MC-deficient Kit W/W-v and Kitl Sl/Sl-d mice are protected from autoantibodymediated models of rheumatoid arthritis and bullous pemphigoid, inflammatory disorders affecting, respectively, the joint and the skin. Reconstitution of Kit W/W-v mice with bone marrow derived, in vitro cultured MCs (BMMCs) restores complete disease susceptibility in both conditions, thus indicating a proinflammatory role of these cells in such diseases. 5,6 Conversely, MCs seem to exert a protective function in experimental autoimmune glomerulonephritis, by limiting clinical and histological glomerular pathology and mortality. 7,8 However, recent work has shown that, unlike Kit W/W-v , Ki...

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“…Treg cells are a family of suppressor T cells which are further divided into two groups: thymicderived 'naturally occurring' Treg cells and induced/adaptive Treg cells generated extra thymically under certain conditions, including autoimmune diseases, transplantation tolerance and tumor immunity. [20][21][22] Accumulating evidence suggests that Treg cells induced in tumor microenvironments are highly immunosuppressive. 23 Relevant to antitumor immunotherapy, experimental models have shown that removal of Treg cells modifies the immune response to tumors.…”

Section: Cd8mentioning

confidence: 99%

Curcumin reverses T cell-mediated adaptive immune dysfunctions in tumor-bearing hosts

et al. 2010

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Immune dysfunction is well documented during tumor progression and likely contributes to tumor immune evasion. CD8 1 cytotoxic T lymphocytes (CTLs) are involved in antigen-specific tumor destruction and CD4 1 T cells are essential for helping this CD8 1 T cell-dependent tumor eradication. Tumors often target and inhibit T-cell function to escape from immune surveillance. This dysfunction includes loss of effector and memory T cells, bias towards type 2 cytokines and expansion of T regulatory (Treg) cells. Curcumin has previously been shown to have antitumor activity and some research has addressed the immunoprotective potential of this plant-derived polyphenol in tumor-bearing hosts. Here we examined the role of curcumin in the prevention of tumor-induced dysfunction of T cell-based immune responses. We observed severe loss of both effector and memory T-cell populations, downregulation of type 1 and upregulation of type 2 immune responses and decreased proliferation of effector T cells in the presence of tumors. Curcumin, in turn, prevented this loss of T cells, expanded central memory T cell (T CM )/effector memory T cell (T EM ) populations, reversed the type 2 immune bias and attenuated the tumor-induced inhibition of T-cell proliferation in tumor-bearing hosts. Further investigation revealed that tumor burden upregulated Treg cell populations and stimulated the production of the immunosuppressive cytokines transforming growth factor (TGF)-b and IL-10 in these cells. Curcumin, however, inhibited the suppressive activity of Treg cells by downregulating the production of TGF-b and IL-10 in these cells. More importantly, curcumin treatment enhanced the ability of effector T cells to kill cancer cells. Overall, our observations suggest that the unique properties of curcumin may be exploited for successful attenuation of tumor-induced suppression of cell-mediated immune responses.

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Blocking angiotensin-converting enzyme induces potent regulatory T cells and modulates TH1- and TH17-mediated autoimmunity

Cited by 285 publications

References 33 publications

Role of the receptor Mas in macrophage-mediated inflammation in vivo

Role of the receptor Mas in macrophage-mediated inflammation in vivo

Exacerbated experimental autoimmune encephalomyelitis in mast-cell-deficient KitW-sh/W-sh mice

Curcumin reverses T cell-mediated adaptive immune dysfunctions in tumor-bearing hosts

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