Interleukin 5 Is Protective during Sepsis in an Eosinophil-Independent Manner

Abstract

Rationale: The immune response in sepsis is characterized by overt immune dysfunction. Studies indicate immunostimulation represents a viable therapy for patients. One study suggests a potentially protective role for interleukin 5 (IL-5) in sepsis; however, the loss of eosinophils in this disease presents a paradox. Objectives: To assess the protective and eosinophil-independent effects of IL-5 in sepsis. Methods: We assessed the effects of IL-5 administration on survival, bacterial burden, and cytokine production after polymicrobial sepsis. In addition, we examined the effects on macrophage phagocytosis and survival using fluorescence microscopy and flow cytometry. Measurements and Main Results: Loss of IL-5 increased mortality and tissue damage in the lung, IL-6 and IL-10 production, and bacterial burden during sepsis. Therapeutic administration of IL-5 improved mortality in sepsis. Interestingly, IL-5 administration resulted in neutrophil recruitment in vivo. IL-5 overexpression in the absence of eosinophils resulted in decreased mortality from sepsis and increased circulating neutrophils and monocytes, suggesting their importance in the protective effects of IL-5. Furthermore, novel data demonstrate IL-5 receptor expression on neutrophils and monocytes in sepsis. IL-5 augmented cytokine secretion, activation, phagocytosis, and survival of macrophages. Importantly, macrophage depletion before the onset of sepsis eliminated IL-5-mediated protection. The protective effects of IL-5 were confirmed in humans, where IL-5 levels were elevated in patients with sepsis. Moreover, neutrophils and monocytes from patients expressed the IL-5 receptor. Conclusions: Taken together, these data support a novel role for IL-5 on noneosinophilic myeloid populations, and suggest treatment with IL-5 may be a viable therapy for sepsis.

IL-33 Precedes IL-5 in Regulating Eosinophil Commitment and Is Required for Eosinophil Homeostasis

“…Moreover, IL-5Rα can also be expressed on neutrophils under certain conditions (30). Therefore, to further confirm that this population we considered to be EoPre cells was truly within the eosinophil lineage, we interrogated the gene expression profiles of these EoPre cells to assess if they expressed eosinophil-associated genes.…”

Microbiota-Regulated IL-25 Increases Eosinophil Number to Provide Protection during Clostridium difficile Infection

“…Currently, eosinophils remain heavily examined in the context of allergy, asthma, and parasitic infection while our understanding of their role in the broader context of bacterial infections remains incomplete. While there has been evidence of eosinophils having antibacterial capabilities in vitro , in vivo correlatives of their role in bacterial infections are limited (Hogan et al, 2013; Linch et al, 2012). Since eosinophils did not reduce the burden of the pathogen, it is likely that their action occurred downstream and involved maintaining the intestinal barrier.…”

Low eosinophil and low lymphocyte counts and the incidence of 12 cardiovascular diseases: a CALIBER cohort study

“…Variants in the IL-5 gene are associated with coronary artery disease,42 and in mouse studies macrophage-specific overexpression of IL-5 led to increased secretion of IgM antibodies that inhibit uptake of oxidised low-density lipoprotein, with consequent inhibition of atherosclerosis 43. In cross-sectional studies, blood levels of IL-5 were strongly associated with eosinophil counts44 and decreased subclinical atherosclerosis,45 and cohort studies among critical care patients found that higher IL-5 was associated with better outcomes 46. We are not aware of any longitudinal cohort studies among the general population which have investigated the association of IL-5 and cardiovascular events; we hypothesise that such an association exists.…”