Human Airway Eosinophils Exhibit Preferential Reduction in STAT Signaling Capacity and Increased CISH Expression

Abstract

Allergic asthma, a chronic respiratory disorder marked by inflammation and recurrent airflow obstruction, is associated with elevated levels of Interleukin-5 (IL-5) family cytokines, and elevated numbers of eosinophils (EOS). IL-5 family cytokines elongate peripheral blood EOS (EOSPB) viability, recruit EOSPB to the airways, and at higher concentrations, induce degranulation and reactive oxygen species (ROS) generation. While, EOSA remain signal ready in that GM-CSF treatment induces degranulation, treatment of EOSA with IL-5 family cytokines no longer confers a survival advantage. Since the IL-5 family receptors have common signaling capacity, but are uncoupled from EOSA survival while other IL-5 family induced endpoints remain functional, we tested the hypothesis that EOSA possess a JAK/STAT specific regulatory mechanism (since JAK/STAT signaling is critical to EOS survival). We found that IL-5 family-induced STAT3 and STAT5 phosphorylation is attenuated in EOSA relative to blood EOS from airway allergen-challenged donors (EOSCPB). However, IL-5 family induced ERK1/2 phosphorylation is not altered between EOSA and EOSCPB. These observations suggest EOSA possess a regulatory mechanism for suppressing STAT signaling distinct from ERK1/2 activation. Furthermore, we found, in EOSPB, IL-5 family cytokines induce members of the suppressors of cytokine signaling (SOCS) genes, CISH and SOCS1. Additionally, following allergen challenge, EOSA express significantly more CISH and SOCS1 mRNA and CISH protein than EOSPB counterparts. In EOSPB, long-term pretreatment with IL-5 family cytokines, to varying degrees, attenuates IL-5 family induced STAT5 phosphorylation. These data support a model wherein IL-5 family cytokines trigger a selective down-regulation mechanism in EOSA for JAK/STAT pathways.

NK cell–derived GM-CSF potentiates inflammatory arthritis and is negatively regulated by CIS

“…IL-3 and IL-5 also signal through the common β chain and can induce Cish expression in common myeloid progenitors and eosinophils, respectively ( Burnham et al, 2013 ; Matsumoto et al, 1997 ; Yoshimura et al, 1995 ). Therefore, CIS deficiency should confer exaggerated cellular responses to these cytokines.…”

Nasal DNA methylation profiling of asthma and rhinitis

“…The following genes have previously been associated with allergic diseases or inflammation: PCSK6, which can activate the NF-kB signaling pathway and is involved in the inflammatory response 36 ; FBXL7, expression of which is involved in the inhaled corticosteroid response in asthma 37 ; and CISH, which showed increased expression levels in human airway eosinophils after allergen challenge. 38 Genes identified by eQTM were enriched in pathways related to immune functions and inflammatory responses.…”

Expression of novel “LOCGEF” isoforms of ARHGEF18 in eosinophils

“…Upon activation with IL5, IL5 receptors become clustered at the tip of the nucleus, and activated JAK2, STAT1, and STAT5 are found in proximity to this cluster [16]. STAT3 is also part of the JAK-STAT signaling pathway and has heretofore not been localized in human eosinophils [45]. After activation with IL5, LOCGEF was concentrated in the nucleopod tip, partially overlapping with STAT3 that was similarly concentrated in the nucleopod (Figure 4B).…”