Macrophages Driven to a Novel State of Activation Have Anti-Inflammatory Properties in Mice

Immunomodulation is a common feature of chronic helminth infections and mainly attributed to the secretion of bioactive molecules, which target and modify host immune cells. In this study, we show that the helminth immunomodulator AvCystatin, a cysteine protease inhibitor, induces a novel regulatory macrophage (Mreg; AvCystatin-Mreg), which is sufficient to mitigate major parameters of allergic airway inflammation and colitis in mice. A single adoptive transfer of AvCystatin-Mreg before allergen challenge suppressed allergen-specific IgE levels, the influx of eosinophils into the airways, local and systemic Th2 cytokine levels, and mucus production in lung bronchioles of mice, whereas increasing local and systemic IL-10 production by CD4+ T cells. Moreover, a single administration of AvCystatin-Mreg during experimentally induced colitis strikingly reduced intestinal pathology. Phenotyping of AvCystatin-Mreg revealed increased expression of a distinct group of genes including LIGHT, sphingosine kinase 1, CCL1, arginase-1, and costimulatory molecules, CD16/32, ICAM-1, as well as PD-L1 and PD-L2. In cocultures with dendritic cells and CD4+ T cells, AvCystatin-Mreg strongly induced the production of IL-10 in a cell-contact–independent manner. Collectively, our data identify a specific suppressive macrophage population induced by a single parasite immunomodulator, which protects against mucosal inflammation.

Section: Discussionmentioning

confidence: 99%

A Novel Regulatory Macrophage Induced by a Helminth Molecule Instructs IL-10 in CD4+ T Cells and Protects against Mucosal Inflammation

Ziegler

Rausch

Steinfelder

et al. 2015

“…Thus, in a skin transplant model, ex vivo exposure of CD4 ϩ T cells to allogeneic bone marrow-derived dendritic cells (DC) cultured in the presence of IFN-␥ has been shown to result in the promotion of a Treg population that prevents allograft rejection (5). In another study, it has been shown that administration of IFN-␥ plus M-CSF-mediated macrophages promotes the clinical and histological resolution of experimental chronic colitis, with enrichment in CD25 ϩ FoxP3 ϩ T cells (6). Delneste et al have previously reported that IFN-␥ inhibits commitment of monocyte (Mo) into DC (7).…”

Section: Ifn-␥ As Secreted During An Alloresponse Induces Differentmentioning

confidence: 99%

IFN-γ, as Secreted during an Alloresponse, Induces Differentiation of Monocytes into Tolerogenic Dendritic Cells, Resulting in FoxP3+ Regulatory T Cell Promotion

Eljaafari

Miossec

2009

IFN-γ has been shown to inhibit monocyte (Mo) differentiation into mature dendritic cells (DC). Because IFN-γ also plays a role in tolerance induction, we asked whether this could be related to generation of tolerogenic DC (Tol-DC). Toward this aim, we cultured Mo with GM-CSF plus IL-4 in the presence or absence of IFN-γ for 6 days and induced their maturation with TNF-α for 2 additional days. We showed that IFN-γ deviated Mo differentiation from mature DC toward Tol-DC. Indeed, IFN-γ-generated DC 1) expressed moderate levels of costimulatory molecules, but high levels of Langerin and CD123 molecules, 2) were maturation resistant, and 3) were unable to efficiently present alloantigen to T cells. More interestingly, naive CD4+ T cells primed with IFN-γ-generated DC expressed FoxP3 mRNA at high levels and exerted regulatory functions upon secondary stimulation with alloantigen. To address whether endogenously secreted IFN-γ mediates a similar effect, we used the alloreaction as a model. We showed that cell-free supernatant harvested from an HLA-mismatched, but not HLA-identical, alloresponse induced differentiation of Mo into Tol-DC able to promote regulatory T cell generation. Moreover, when supplemented with GM-CSF plus IL-4, HLA-mismatched cell-free supernatant inhibited differentiation of Mo into mature DC. Finally, by adding Abs directed against inflammatory cytokines, we demonstrated that IFN-γ plays a preponderant role in this inhibition. In conclusion, our results clearly demonstrate that exogenous or endogenous IFN-γ, as well, induces differentiation of Mo toward Tol-DC, which results in FoxP3+ regulatory T cell promotion.

“…Other myeloid cells, such as CD40L-and IFN-g2treated macrophages (38) and some MDSCs (39), were shown to regulate CD4 + T cell activation because of the induction of Tregs. Therefore, we analyzed whether CD4 + T cells expressed Foxp3 (Fig.…”

Section: Gcsms Induce Foxp3 + Tregs Through Repetitive Stimulation Ofmentioning

confidence: 99%

Immune Suppression via Glucocorticoid-Stimulated Monocytes: A Novel Mechanism To Cope with Inflammation

Varga

Ehrchen

Brockhausen

et al. 2014

Glucocorticoids (GCs) are used as first-line therapies for generalized suppression of inflammation (e.g., allergies or autoimmune diseases), but their long-term use is limited by severe side effects. Our previous work revealed that GCs induced a stable anti-inflammatory phenotype in monocytes, the GC-stimulated monocytes (GCsMs) that we exploited for targeted GC-mediated therapeutic effects. We demonstrate that GCsMs interact with T cells in suppressing proliferation, as well as cytokine release of CD8+ and, especially, CD4+ T cells in vitro, and that they support generation of Foxp3+ cells. Therefore, we tested their immunosuppressive potential in CD4+ T cell–induced colitis in vivo. We found that injection of GCsMs into mice with severe colitis abolished the inflammation and resulted in significant clinical improvement within a few days. T cells recovered from GCsM-treated mice exhibited reduced secretion of proinflammatory cytokines IFN-γ and IL-17. Furthermore, clusters of Foxp3+ CD4+ T cells were detectable at local sites of inflammation in the colon. Thus, GCsMs are able to modify T cell responses in vitro and in vivo, as well as to downregulate and clinically cure severe T cell–mediated colitis.