Antibodies to Complement Receptor 3 Treat Established Inflammation in Murine Models of Colitis and a Novel Model of Psoriasiform Dermatitis

León, Francisco; Contractor, Nikhat; Fuss, Ivan J.; Marth, Thomas; Lahey, Edward; Iwaki, Shoko; Sala, A.; Hoffmann, Victoria; Strober, Warren; Kelsall, Brian L.

doi:10.4049/jimmunol.177.10.6974

Cited by 43 publications

(40 citation statements)

References 44 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Clearly, immune cells can trigger this crosstalk, as shown by the induction of psoriasiform, inflammatory skin lesions in mice by transfer of CD4+CD45RBhi T cells into T cell deficient Rag22/2 mice (Leon et al, 2006). However, also keratinocytes are able to initiate immune system activation.…”

Section: Discussionmentioning

confidence: 99%

RAC1 in keratinocytes regulates crosstalk to immune cells by Arp2/3 dependent control of STAT1

Pedersen

Wang

Stanley

et al. 2012

Journal of Cell Science

View full text Add to dashboard Cite

SummaryCrosstalk between keratinocytes and immune cells is crucial for the immunological barrier function of the skin, and aberrant crosstalk contributes to inflammatory skin diseases. Using mice with a keratinocyte-restricted deletion of the RAC1 gene we found that RAC1 in keratinocytes plays an important role in modulating the interferon (IFN) response in skin. These RAC1 mutant mice showed increased sensitivity in an irritant contact dermatitis model, abnormal keratinocyte differentiation, and increased expression of immune response genes including the IFN signal transducer STAT1. Loss of RAC1 in keratinocytes decreased actin polymerization in vivo and in vitro and caused Arp2/3-dependent expression of STAT1, increased interferon sensitivity and upregulation of aberrant keratinocyte differentiation markers. This can be inhibited by the AP-1 inhibitor tanshinone IIA. Loss of RAC1 makes keratinocytes hypersensitive to inflammatory stimuli both in vitro and in vivo, suggesting a major role for RAC1 in regulating the crosstalk between the epidermis and the immune system.

show abstract

Section: Discussionmentioning

confidence: 99%

RAC1 in keratinocytes regulates crosstalk to immune cells by Arp2/3 dependent control of STAT1

Pedersen

Wang

Stanley

et al. 2012

Journal of Cell Science

View full text Add to dashboard Cite

show abstract

“…Nonetheless, our data do not in any way diminish the possibility of using artificial ligation of CR3 as a means of manipulating DC function, because supraphysiologic activation of CR3 can clearly modulate DCs toward an anti-inflammatory phenotype (8 -10). Data already exist to suggest that the activation of CR3 via mAb may be useful in treating psoriasis and inflammatory colitis in mouse models of these diseases (42). However, it is important to put the role of CR3 in a physiologic context with respect to apoptotic cell processing and continuing to study the physiologic roles of CR3 will help us to understand how to best pursue its potential pharmacologic utility.…”

Section: Discussionmentioning

confidence: 99%

Apoptotic Cell-Mediated Immunoregulation of Dendritic Cells Does Not Require iC3b Opsonization

Behrens

Ning

Muvarak

et al. 2008

The Journal of Immunology

View full text Add to dashboard Cite

A number of recent studies show that activation of CR3 on dendritic cells (DCs) suppresses TLR-induced TNF-α and IL-12 production and inhibits effective Ag presentation. Although the proposed physiologic role for these phenomena is immune suppression due to recognition of iC3b opsonized apoptotic cells by CR3, all of the aforementioned investigations used artificial means of activating CR3. We investigated whether iC3b opsonized apoptotic cells could induce the same changes reported with artificial ligands such as mAbs or iC3b-opsonized RBC. We explored the kinetics of iC3b opsonization in two models of murine cell apoptosis, γ-irradiated thymocytes and cytokine deprivation of the IL-3 dependent cell line BaF3. Using a relatively homogenous population of early apoptotic cells (IL-3 deprived BaF3 cells), we show that iC3b opsonized apoptotic cells engage CR3, but this interaction is dispensable in mediating the anti-inflammatory effects of apoptotic cells. TLR-induced TNF-α and IL-12 production by bone marrow-derived DCs occurs heterogeneously, with apoptotic cells inhibiting only certain populations depending on the TLR agonist. In contrast, although apoptotic cells induced homogeneous IL-10 production by DCs, IL-10 was not necessary for the inhibition of TNF-α and IL-12. Furthermore, because the ability of iC3b opsonization to enhance phagocytosis of apoptotic cells has been controversial, we report that iC3b opsonization does not significantly affect apoptotic cell ingestion by DCs. We conclude that the apoptotic cell receptor system on DCs is sufficiently redundant such that the absence of CR3 engagement does not significantly affect the normal anti-inflammatory processing of apoptotic cells.

show abstract

“…21,39 To determine whether phagocytosis of DAF/Crry-deficient platelets was mediated by these receptors, we transfused DAF/Crry-deficient platelets into mice that lacked functional CR3 or CRIg as a result of antibody blocking or gene deletion. 21,22,40,41 As shown in Figure 4E, antibody blocking of CR3 in WT mice or genetic disruption of CR3 (CD11b gene knockout) had no effect on the accelerated elimination of DAF/Crry-deficient platelets. Moreover, antibody blocking of CR1/2 in WT mice or CR4 in CR3 Ϫ/Ϫ mice did not rescue the transfused DAF/Crry-deficient platelets.…”

Section: Phagocytosis Of Daf/crry-deficient Platelets Was Mediated Bymentioning

confidence: 99%

Deficiency of decay-accelerating factor and complement receptor 1–related gene/protein y on murine platelets leads to complement-dependent clearance by the macrophage phagocytic receptor CRIg

Kim

Miwa

Kimura

et al. 2008

Blood

View full text Add to dashboard Cite

Complement activation on human platelets is known to cause platelet degranulation and activation. To evaluate how normal platelets escape complement attack in vivo, we studied the fate of murine platelets deficient in 2 membrane complement regulatory proteins using an adoptive transfer model. We show here that deficiency of either decay-accelerating factor (DAF) or complement receptor 1-related gene/protein y (Crry) on murine platelets was inconsequential, whereas DAF and Crry double deficiency led to rapid clearance of platelets from circulation in a complement-and macrophagedependent manner. This finding contrasted with the observation on erythrocytes, where Crry deficiency alone resulted in complement susceptibility. Quantitative flow cytometry revealed that DAF and Crry were expressed at similar levels on platelets, whereas Crry expression was 3 times higher than DAF on erythrocytes. Antibody blocking or gene ablation of the newly identified complement receptor CRIg, but not complement receptor 3 (CR3), rescued DAF/Crry-deficient platelets from complement-dependent elimination. Surprisingly, deficiency of CRIg, CR3, and other known complement receptors failed to prevent Crrydeficient erythrocytes from complementmediated clearance. These results show a critical but redundant role of DAF and Crry in platelet survival and suggest that complement-opsonized platelets and erythrocytes engage different complement receptors on tissue macrophages in

show abstract

Antibodies to Complement Receptor 3 Treat Established Inflammation in Murine Models of Colitis and a Novel Model of Psoriasiform Dermatitis

Cited by 43 publications

References 44 publications

RAC1 in keratinocytes regulates crosstalk to immune cells by Arp2/3 dependent control of STAT1

RAC1 in keratinocytes regulates crosstalk to immune cells by Arp2/3 dependent control of STAT1

Apoptotic Cell-Mediated Immunoregulation of Dendritic Cells Does Not Require iC3b Opsonization

Deficiency of decay-accelerating factor and complement receptor 1–related gene/protein y on murine platelets leads to complement-dependent clearance by the macrophage phagocytic receptor CRIg

Contact Info

Product

Resources

About