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Switching off key signaling survival molecules to switch on the resolution of inflammation.

Perez DA, Vago JP, Athayde RM, Reis AC, Teixeira MM, Sousa LP, Pinho V - Mediators Inflamm. (2014)

Bottom Line: Inflammation is a physiological response of the immune system to injury or infection but may become chronic.It has been argued that unresolved inflammation may be the basis of a variety of chronic inflammatory diseases.Here, we explore key signaling molecules and some mediators that are crucial regulators of leukocyte survival in vivo and that may be targeted for therapeutic purposes in the context of chronic inflammatory diseases.

View Article: PubMed Central - PubMed

Affiliation: Laboratório de Resolução da Resposta Inflamatória, Departamento de Morfologia, Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais, Avenida Antônio Carlos 6627, Pampulha, 31270-901 Belo Horizonte, MG, Brazil ; Laboratório de Imunofarmacologia, Departamento de Bioquímica e Imunologia, Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais, 31270-901 Belo Horizonte, MG, Brazil.

ABSTRACT
Inflammation is a physiological response of the immune system to injury or infection but may become chronic. In general, inflammation is self-limiting and resolves by activating a termination program named resolution of inflammation. It has been argued that unresolved inflammation may be the basis of a variety of chronic inflammatory diseases. Resolution of inflammation is an active process that is fine-tuned by the production of proresolving mediators and the shutdown of intracellular signaling molecules associated with cytokine production and leukocyte survival. Apoptosis of leukocytes (especially granulocytes) is a key element in the resolution of inflammation and several signaling molecules are thought to be involved in this process. Here, we explore key signaling molecules and some mediators that are crucial regulators of leukocyte survival in vivo and that may be targeted for therapeutic purposes in the context of chronic inflammatory diseases.

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Related in: MedlinePlus

Targets to promote granulocyte apoptosis and inflammation resolution. During early phase of inflammation production of proinflammatory mediators and activation of signal survival pathways (PI3K/Akt, NF-κB, MAPKs, and CDKs) promotes leukocyte accumulation and survival in the inflammatory site. While inflammatory response evolves, local activation/release of proresolution mediators occurs and pathways (H2O2, AnxA1, and cAMP) that control further granulocyte ingress and turn on a resolution program. These resolution molecules, in addition to proresolving lipid mediators which are not highlighted in this cartoon, downregulate survival pathways and activate an apoptosis-associated program in granulocytes. Resolution molecules are also able to promote efferocytosis and coordinate reprogramming of macrophages. These events will reestablish tissue homeostasis.
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fig1: Targets to promote granulocyte apoptosis and inflammation resolution. During early phase of inflammation production of proinflammatory mediators and activation of signal survival pathways (PI3K/Akt, NF-κB, MAPKs, and CDKs) promotes leukocyte accumulation and survival in the inflammatory site. While inflammatory response evolves, local activation/release of proresolution mediators occurs and pathways (H2O2, AnxA1, and cAMP) that control further granulocyte ingress and turn on a resolution program. These resolution molecules, in addition to proresolving lipid mediators which are not highlighted in this cartoon, downregulate survival pathways and activate an apoptosis-associated program in granulocytes. Resolution molecules are also able to promote efferocytosis and coordinate reprogramming of macrophages. These events will reestablish tissue homeostasis.

Mentions: Several signaling molecules, including PI3K/Akt, NF-κB, MAPKs, and CDKs, have been shown to be involved in enhancing granulocyte survival in vivo and in vitro [13–16]. The rationale behind enhanced granulocyte survival involves delaying death of these cells to enable efficient effector function, such as bacterial killing. However, if not finely controlled, prolonged activation of survival pathways and prevention of apoptosis in granulocytes may eventually delay inflammation resolution. In contrast with the molecules described above, proresolving mediators, including Annexin A1 (AnxA1), hydrogen peroxide (H2O2), cyclic adenosine monophosphate (cAMP), TNF-related apoptosis-inducing ligand (TRAIL) elevating agents (see Figure 1), and other specialized lipid mediators (lipoxin A4, resolvins, maresins, and protectins), perform the opposite action; that is, they induce granulocyte apoptosis. Recent studies have shown that strategies that modulate apoptosis-controlling proteins may promote the resolution of the inflammatory process [17–22]. Therefore, potential therapeutic strategies that modulate the resolution pathways may further represent a useful pharmacological arsenal for the treatment and prevention of various acute and chronic inflammatory diseases. Here, we discuss some aspects of the complex signaling network and some interventions that interfere with key signaling molecules associated with leukocyte survival and consequently contribute to inflammation resolution and return to homeostasis.


Switching off key signaling survival molecules to switch on the resolution of inflammation.

Perez DA, Vago JP, Athayde RM, Reis AC, Teixeira MM, Sousa LP, Pinho V - Mediators Inflamm. (2014)

Targets to promote granulocyte apoptosis and inflammation resolution. During early phase of inflammation production of proinflammatory mediators and activation of signal survival pathways (PI3K/Akt, NF-κB, MAPKs, and CDKs) promotes leukocyte accumulation and survival in the inflammatory site. While inflammatory response evolves, local activation/release of proresolution mediators occurs and pathways (H2O2, AnxA1, and cAMP) that control further granulocyte ingress and turn on a resolution program. These resolution molecules, in addition to proresolving lipid mediators which are not highlighted in this cartoon, downregulate survival pathways and activate an apoptosis-associated program in granulocytes. Resolution molecules are also able to promote efferocytosis and coordinate reprogramming of macrophages. These events will reestablish tissue homeostasis.
© Copyright Policy - open-access
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC4127222&req=5

fig1: Targets to promote granulocyte apoptosis and inflammation resolution. During early phase of inflammation production of proinflammatory mediators and activation of signal survival pathways (PI3K/Akt, NF-κB, MAPKs, and CDKs) promotes leukocyte accumulation and survival in the inflammatory site. While inflammatory response evolves, local activation/release of proresolution mediators occurs and pathways (H2O2, AnxA1, and cAMP) that control further granulocyte ingress and turn on a resolution program. These resolution molecules, in addition to proresolving lipid mediators which are not highlighted in this cartoon, downregulate survival pathways and activate an apoptosis-associated program in granulocytes. Resolution molecules are also able to promote efferocytosis and coordinate reprogramming of macrophages. These events will reestablish tissue homeostasis.
Mentions: Several signaling molecules, including PI3K/Akt, NF-κB, MAPKs, and CDKs, have been shown to be involved in enhancing granulocyte survival in vivo and in vitro [13–16]. The rationale behind enhanced granulocyte survival involves delaying death of these cells to enable efficient effector function, such as bacterial killing. However, if not finely controlled, prolonged activation of survival pathways and prevention of apoptosis in granulocytes may eventually delay inflammation resolution. In contrast with the molecules described above, proresolving mediators, including Annexin A1 (AnxA1), hydrogen peroxide (H2O2), cyclic adenosine monophosphate (cAMP), TNF-related apoptosis-inducing ligand (TRAIL) elevating agents (see Figure 1), and other specialized lipid mediators (lipoxin A4, resolvins, maresins, and protectins), perform the opposite action; that is, they induce granulocyte apoptosis. Recent studies have shown that strategies that modulate apoptosis-controlling proteins may promote the resolution of the inflammatory process [17–22]. Therefore, potential therapeutic strategies that modulate the resolution pathways may further represent a useful pharmacological arsenal for the treatment and prevention of various acute and chronic inflammatory diseases. Here, we discuss some aspects of the complex signaling network and some interventions that interfere with key signaling molecules associated with leukocyte survival and consequently contribute to inflammation resolution and return to homeostasis.

Bottom Line: Inflammation is a physiological response of the immune system to injury or infection but may become chronic.It has been argued that unresolved inflammation may be the basis of a variety of chronic inflammatory diseases.Here, we explore key signaling molecules and some mediators that are crucial regulators of leukocyte survival in vivo and that may be targeted for therapeutic purposes in the context of chronic inflammatory diseases.

View Article: PubMed Central - PubMed

Affiliation: Laboratório de Resolução da Resposta Inflamatória, Departamento de Morfologia, Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais, Avenida Antônio Carlos 6627, Pampulha, 31270-901 Belo Horizonte, MG, Brazil ; Laboratório de Imunofarmacologia, Departamento de Bioquímica e Imunologia, Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais, 31270-901 Belo Horizonte, MG, Brazil.

ABSTRACT
Inflammation is a physiological response of the immune system to injury or infection but may become chronic. In general, inflammation is self-limiting and resolves by activating a termination program named resolution of inflammation. It has been argued that unresolved inflammation may be the basis of a variety of chronic inflammatory diseases. Resolution of inflammation is an active process that is fine-tuned by the production of proresolving mediators and the shutdown of intracellular signaling molecules associated with cytokine production and leukocyte survival. Apoptosis of leukocytes (especially granulocytes) is a key element in the resolution of inflammation and several signaling molecules are thought to be involved in this process. Here, we explore key signaling molecules and some mediators that are crucial regulators of leukocyte survival in vivo and that may be targeted for therapeutic purposes in the context of chronic inflammatory diseases.

Show MeSH
Related in: MedlinePlus