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Priming dendritic cells for th2 polarization: lessons learned from helminths and implications for metabolic disorders.

Hussaarts L, Yazdanbakhsh M, Guigas B - Front Immunol (2014)

Bottom Line: A common feature of helminth infections is the manifestation of a type 2 immune response, characterized by T helper 2 (Th2) cells that mediate anti-helminth immunity.The molecular mechanisms that govern Th2 responses are poorly understood, although it is clear that dendritic cells (DCs), which are the most efficient antigen-presenting cells in the immune system, play a central role.Finally, we discuss the implication of these findings in the context of metabolic disorders, as recent literature indicates that various aspects of the Th2-associated inflammatory response contribute to metabolic homeostasis.

View Article: PubMed Central - PubMed

Affiliation: Department of Parasitology, Leiden University Medical Center , Leiden , Netherlands.

ABSTRACT
Nearly one quarter of the world's population is infected with helminth parasites. A common feature of helminth infections is the manifestation of a type 2 immune response, characterized by T helper 2 (Th2) cells that mediate anti-helminth immunity. In addition, recent literature describes a close association between type 2 immune responses and wound repair, suggesting that a Th2 response may concurrently mediate repair of parasite-induced damage. The molecular mechanisms that govern Th2 responses are poorly understood, although it is clear that dendritic cells (DCs), which are the most efficient antigen-presenting cells in the immune system, play a central role. Here, we review the molecular mechanisms by which DCs polarize Th2 cells, examining both helminth antigens and helminth-mediated tissue damage as Th2-inducing triggers. Finally, we discuss the implication of these findings in the context of metabolic disorders, as recent literature indicates that various aspects of the Th2-associated inflammatory response contribute to metabolic homeostasis.

No MeSH data available.


Related in: MedlinePlus

Possible mechanisms by which helminth molecules modulate DCs for Th2 polarization. Helminth antigens are recognized by DCs through ligation of pattern recognition receptors (PRRs), such as Toll-like receptors (TLRs) and C-type lectin receptors (CLRs). Depending on the antigen, binding promotes phosphorylation of ERK1/2, nuclear accumulation of NF-κB or Bcl3, and/or activation of the Nlrp3 inflammasome, which mediates IL-1β secretion. Phosphorylation of ERK1/2 stabilizes c-Fos, leading to downregulation of IL-12 expression. In addition, DCs can upregulate expression of Th2-associated CD40 and Jagged, which are under the control of NF-κB and ERK1/2, respectively (115, 116). Upon encounter of T cells expressing CD40L, signaling through CD40 promotes OX40L expression in an autocrine manner. Alternatively, PRRs may mediate uptake of antigens that interfere with antigen presentation on MHCs, such as cystatins, or RNases that inhibit protein synthesis, thereby suppressing the expression of costimulatory molecules like CD80 and CD86. These events affect T cell receptor (TCR) signaling. As a consequence of protein synthesis inhibition, RNases may also downregulate Th1-polarizing cytokines or molecules like IL-12 and Delta-4. In parallel, helminths or their eggs damage epithelium, and alarmins are released, such as thymic stromal lymphopoietin (TSLP) and IL-33, which bind the TSLP receptor (TSLPR) and T1/ST2, respectively. TSLP can also activate ERK1/2, STAT5, and NF-kB to promote CD40 and OX40L expression. Altogether, these events favor DC-mediated Th2 polarization.
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Figure 1: Possible mechanisms by which helminth molecules modulate DCs for Th2 polarization. Helminth antigens are recognized by DCs through ligation of pattern recognition receptors (PRRs), such as Toll-like receptors (TLRs) and C-type lectin receptors (CLRs). Depending on the antigen, binding promotes phosphorylation of ERK1/2, nuclear accumulation of NF-κB or Bcl3, and/or activation of the Nlrp3 inflammasome, which mediates IL-1β secretion. Phosphorylation of ERK1/2 stabilizes c-Fos, leading to downregulation of IL-12 expression. In addition, DCs can upregulate expression of Th2-associated CD40 and Jagged, which are under the control of NF-κB and ERK1/2, respectively (115, 116). Upon encounter of T cells expressing CD40L, signaling through CD40 promotes OX40L expression in an autocrine manner. Alternatively, PRRs may mediate uptake of antigens that interfere with antigen presentation on MHCs, such as cystatins, or RNases that inhibit protein synthesis, thereby suppressing the expression of costimulatory molecules like CD80 and CD86. These events affect T cell receptor (TCR) signaling. As a consequence of protein synthesis inhibition, RNases may also downregulate Th1-polarizing cytokines or molecules like IL-12 and Delta-4. In parallel, helminths or their eggs damage epithelium, and alarmins are released, such as thymic stromal lymphopoietin (TSLP) and IL-33, which bind the TSLP receptor (TSLPR) and T1/ST2, respectively. TSLP can also activate ERK1/2, STAT5, and NF-kB to promote CD40 and OX40L expression. Altogether, these events favor DC-mediated Th2 polarization.

Mentions: In addition to signaling-dependent mechanisms, various helminth products harbor enzymatic activities that mediate Th2 skewing. For example, omega-1 depends on its RNase activity, which allows the molecule to cleave both ribosomal and messenger RNA, to downmodulate TLR-induced moDC maturation and IL-12 production, and to skew toward Th2 (40). Interestingly, various Th2-inducing allergens are also RNases (68, 69), as well as the endogenous eosinophil-derived neurotoxin that can amplify DC-mediated Th2 polarization (70). Together, these reports suggest that any RNase internalized by DCs may harbor Th2-priming capacities, through cleavage of ribosomal and/or messenger RNA. Similarly, a number of studies identified a role for cysteine protease inhibitors secreted by filarial nematodes (cystatins) in regulating host immune responses by interfering with antigen processing [reviewed in Ref. (71)]. Therefore, helminths may employ both signaling-dependent and independent mechanisms to condition DCs for Th2 skewing (Figure 1).


Priming dendritic cells for th2 polarization: lessons learned from helminths and implications for metabolic disorders.

Hussaarts L, Yazdanbakhsh M, Guigas B - Front Immunol (2014)

Possible mechanisms by which helminth molecules modulate DCs for Th2 polarization. Helminth antigens are recognized by DCs through ligation of pattern recognition receptors (PRRs), such as Toll-like receptors (TLRs) and C-type lectin receptors (CLRs). Depending on the antigen, binding promotes phosphorylation of ERK1/2, nuclear accumulation of NF-κB or Bcl3, and/or activation of the Nlrp3 inflammasome, which mediates IL-1β secretion. Phosphorylation of ERK1/2 stabilizes c-Fos, leading to downregulation of IL-12 expression. In addition, DCs can upregulate expression of Th2-associated CD40 and Jagged, which are under the control of NF-κB and ERK1/2, respectively (115, 116). Upon encounter of T cells expressing CD40L, signaling through CD40 promotes OX40L expression in an autocrine manner. Alternatively, PRRs may mediate uptake of antigens that interfere with antigen presentation on MHCs, such as cystatins, or RNases that inhibit protein synthesis, thereby suppressing the expression of costimulatory molecules like CD80 and CD86. These events affect T cell receptor (TCR) signaling. As a consequence of protein synthesis inhibition, RNases may also downregulate Th1-polarizing cytokines or molecules like IL-12 and Delta-4. In parallel, helminths or their eggs damage epithelium, and alarmins are released, such as thymic stromal lymphopoietin (TSLP) and IL-33, which bind the TSLP receptor (TSLPR) and T1/ST2, respectively. TSLP can also activate ERK1/2, STAT5, and NF-kB to promote CD40 and OX40L expression. Altogether, these events favor DC-mediated Th2 polarization.
© Copyright Policy - open-access
Related In: Results  -  Collection

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Show All Figures
getmorefigures.php?uid=PMC4202775&req=5

Figure 1: Possible mechanisms by which helminth molecules modulate DCs for Th2 polarization. Helminth antigens are recognized by DCs through ligation of pattern recognition receptors (PRRs), such as Toll-like receptors (TLRs) and C-type lectin receptors (CLRs). Depending on the antigen, binding promotes phosphorylation of ERK1/2, nuclear accumulation of NF-κB or Bcl3, and/or activation of the Nlrp3 inflammasome, which mediates IL-1β secretion. Phosphorylation of ERK1/2 stabilizes c-Fos, leading to downregulation of IL-12 expression. In addition, DCs can upregulate expression of Th2-associated CD40 and Jagged, which are under the control of NF-κB and ERK1/2, respectively (115, 116). Upon encounter of T cells expressing CD40L, signaling through CD40 promotes OX40L expression in an autocrine manner. Alternatively, PRRs may mediate uptake of antigens that interfere with antigen presentation on MHCs, such as cystatins, or RNases that inhibit protein synthesis, thereby suppressing the expression of costimulatory molecules like CD80 and CD86. These events affect T cell receptor (TCR) signaling. As a consequence of protein synthesis inhibition, RNases may also downregulate Th1-polarizing cytokines or molecules like IL-12 and Delta-4. In parallel, helminths or their eggs damage epithelium, and alarmins are released, such as thymic stromal lymphopoietin (TSLP) and IL-33, which bind the TSLP receptor (TSLPR) and T1/ST2, respectively. TSLP can also activate ERK1/2, STAT5, and NF-kB to promote CD40 and OX40L expression. Altogether, these events favor DC-mediated Th2 polarization.
Mentions: In addition to signaling-dependent mechanisms, various helminth products harbor enzymatic activities that mediate Th2 skewing. For example, omega-1 depends on its RNase activity, which allows the molecule to cleave both ribosomal and messenger RNA, to downmodulate TLR-induced moDC maturation and IL-12 production, and to skew toward Th2 (40). Interestingly, various Th2-inducing allergens are also RNases (68, 69), as well as the endogenous eosinophil-derived neurotoxin that can amplify DC-mediated Th2 polarization (70). Together, these reports suggest that any RNase internalized by DCs may harbor Th2-priming capacities, through cleavage of ribosomal and/or messenger RNA. Similarly, a number of studies identified a role for cysteine protease inhibitors secreted by filarial nematodes (cystatins) in regulating host immune responses by interfering with antigen processing [reviewed in Ref. (71)]. Therefore, helminths may employ both signaling-dependent and independent mechanisms to condition DCs for Th2 skewing (Figure 1).

Bottom Line: A common feature of helminth infections is the manifestation of a type 2 immune response, characterized by T helper 2 (Th2) cells that mediate anti-helminth immunity.The molecular mechanisms that govern Th2 responses are poorly understood, although it is clear that dendritic cells (DCs), which are the most efficient antigen-presenting cells in the immune system, play a central role.Finally, we discuss the implication of these findings in the context of metabolic disorders, as recent literature indicates that various aspects of the Th2-associated inflammatory response contribute to metabolic homeostasis.

View Article: PubMed Central - PubMed

Affiliation: Department of Parasitology, Leiden University Medical Center , Leiden , Netherlands.

ABSTRACT
Nearly one quarter of the world's population is infected with helminth parasites. A common feature of helminth infections is the manifestation of a type 2 immune response, characterized by T helper 2 (Th2) cells that mediate anti-helminth immunity. In addition, recent literature describes a close association between type 2 immune responses and wound repair, suggesting that a Th2 response may concurrently mediate repair of parasite-induced damage. The molecular mechanisms that govern Th2 responses are poorly understood, although it is clear that dendritic cells (DCs), which are the most efficient antigen-presenting cells in the immune system, play a central role. Here, we review the molecular mechanisms by which DCs polarize Th2 cells, examining both helminth antigens and helminth-mediated tissue damage as Th2-inducing triggers. Finally, we discuss the implication of these findings in the context of metabolic disorders, as recent literature indicates that various aspects of the Th2-associated inflammatory response contribute to metabolic homeostasis.

No MeSH data available.


Related in: MedlinePlus