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Interleukin-4 Antagonizes Neutrophil Functions during Acute Bacterial Infection


Woytschak, Janine. Interleukin-4 Antagonizes Neutrophil Functions during Acute Bacterial Infection. 2016, University of Zurich, Faculty of Science.

Abstract

Neutrophils belong to the innate immune system and are usually the first cell type recruited from the bone marrow and periphery to a site of inflammation. Neutrophils exert multiple effector functions to modulate inflammation and fight invading pathogens. Defects in their generation, recruitment or effector functions can lead to severe disease states. It has been shown that patients suffering from T helper 2 cell (Th2)-mediated diseases are more prone to bacterial infections, suggesting a negative effect of Th2-type immune responses on anti-bacterial immunity. We hypothesized that interleukin-4 (IL-4), a central cytokine driving and maintaining Th2 immunity, could affect neutrophils and lead to increased susceptibility towards infections.
Acute bacterial infection led to expansion and migration from the bone marrow (BM) to blood and spleen of CD11b+ Ly6G+ neutrophils, which was dependent on granulocyte colony-stimulating factor (G-CSF). Similarly, injection of long-acting G-CSF, in the form of G-CSF/anti-G-CSF antibody complexes (G-CSFcx), caused expansion and migration of neutrophils. Significantly, IL-4, in the form of long-acting IL-4/anti-IL-4 antibody complexes (IL-4cx), antagonized the effects of G-CSF both following bacterial infection and G-CSFcx administration. This inhibitory effect of IL-4cx was mediated by direct binding of IL-4 to neutrophils, in particular to the type II IL-4 receptor (IL-4R) present on neutrophils. G-CSFcx enhanced type II IL-4R expression on neutrophils, thereby making them even more responsive towards IL-4. Mice treated with G-CSFcx were able to survive systemic Listeria monocytogenes infection, whereas co-administration of IL-4cx led to mortality rates comparable to untreated mice. Furthermore IL-4R deficiency protected from lethal Listeria monocytogenes infection. IL-4cx decreased neutrophil egress from BM by CXCR4 upregulation on neutrophils, as well as decreased CXCR2 expression in splenic neutrophils. Moreover, IL-4 signals inhibited, via the p38 MAPK pathway, the migration in vitro and in vivo of neutrophils towards CXCR2-binding chemokines. Notably, the migration capacity of neutrophils into skin lesions infected with group A Streptococcus was dampened in animals receiving IL-4cx, leading to more severe disease; in contrast, neutralizing endogenously produced IL-4 led to smaller skin lesions and more rapid bacterial clearance in mice. IL-4 signals also diminished the production of reactive oxygen species by neutrophils.
These data show a previously unknown role of the IL-4type II IL-4R pathway in affecting multiple functions of neutrophils and thereby impacting anti-bacterial immunity.

Abstract

Neutrophils belong to the innate immune system and are usually the first cell type recruited from the bone marrow and periphery to a site of inflammation. Neutrophils exert multiple effector functions to modulate inflammation and fight invading pathogens. Defects in their generation, recruitment or effector functions can lead to severe disease states. It has been shown that patients suffering from T helper 2 cell (Th2)-mediated diseases are more prone to bacterial infections, suggesting a negative effect of Th2-type immune responses on anti-bacterial immunity. We hypothesized that interleukin-4 (IL-4), a central cytokine driving and maintaining Th2 immunity, could affect neutrophils and lead to increased susceptibility towards infections.
Acute bacterial infection led to expansion and migration from the bone marrow (BM) to blood and spleen of CD11b+ Ly6G+ neutrophils, which was dependent on granulocyte colony-stimulating factor (G-CSF). Similarly, injection of long-acting G-CSF, in the form of G-CSF/anti-G-CSF antibody complexes (G-CSFcx), caused expansion and migration of neutrophils. Significantly, IL-4, in the form of long-acting IL-4/anti-IL-4 antibody complexes (IL-4cx), antagonized the effects of G-CSF both following bacterial infection and G-CSFcx administration. This inhibitory effect of IL-4cx was mediated by direct binding of IL-4 to neutrophils, in particular to the type II IL-4 receptor (IL-4R) present on neutrophils. G-CSFcx enhanced type II IL-4R expression on neutrophils, thereby making them even more responsive towards IL-4. Mice treated with G-CSFcx were able to survive systemic Listeria monocytogenes infection, whereas co-administration of IL-4cx led to mortality rates comparable to untreated mice. Furthermore IL-4R deficiency protected from lethal Listeria monocytogenes infection. IL-4cx decreased neutrophil egress from BM by CXCR4 upregulation on neutrophils, as well as decreased CXCR2 expression in splenic neutrophils. Moreover, IL-4 signals inhibited, via the p38 MAPK pathway, the migration in vitro and in vivo of neutrophils towards CXCR2-binding chemokines. Notably, the migration capacity of neutrophils into skin lesions infected with group A Streptococcus was dampened in animals receiving IL-4cx, leading to more severe disease; in contrast, neutralizing endogenously produced IL-4 led to smaller skin lesions and more rapid bacterial clearance in mice. IL-4 signals also diminished the production of reactive oxygen species by neutrophils.
These data show a previously unknown role of the IL-4type II IL-4R pathway in affecting multiple functions of neutrophils and thereby impacting anti-bacterial immunity.

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Additional indexing

Item Type:Dissertation
Referees:Boyman Onur
Communities & Collections:04 Faculty of Medicine > University Hospital Zurich > Clinic for Immunology
Dewey Decimal Classification:610 Medicine & health
Language:English
Date:2016
Deposited On:08 Feb 2017 15:56
Last Modified:03 Mar 2017 09:16

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