All ETDs from UAB

Advisory Committee Chair

Amit Gaggar

Advisory Committee Members

Thomas P Atkinson

David D Chaplin

Alexander J Szalai

Document Type

Dissertation

Date of Award

2020

Degree Name by School

Doctor of Philosophy (PhD) Heersink School of Medicine

Abstract

Asthma patients are increasingly presenting with asthma that is more difficult to control and treat than in years past. A subset of these patients who are sensitive to fungal species are described as having severe asthma with fungal sensitization (SAFS). Given the severity of disease, there is ever increasing interest in identifying the immune processes underlying SAFS disease pathology and the development of novel therapeutics to improve management. While sensitivity to multiple fungal species has been described in SAFS, none is more common than Aspergillus fumigatus. Here, we describe two previously unrecognized contributors to the amelioration of disease pathology in a murine model of fungal-associated allergic asthma, the IL-1 receptor antagonist (IL-1Ra) and chemokine (C-X3-C motif) ligand 1 (CX3CL1). Initial identification of these mediators was brought about by analysis of samples from cohorts of patients who were (fungal positive) or were not (fungal negative) sensitive to fungi. Using mice deficient in either the type one IL-1 receptor (Il1r1 -/- mice) or IL-1Ra (Il1rn -/- mice) we demonstrate that absence of IL-1 signaling (Il1r1 -/-) leads to reduction of type 1 (IFN-gamma, CXCL9, CXCL10) and type 17 (IL-17A, IL-22) responses that were associated with airway hyperresponsiveness (AHR) and increased neutrophil infiltration while dysregulated signaling (Il1rn -/-) exacerbates these responses. Moreover, we show that treating mice with human recombinant IL-1Ra (anakinra) reduces AHR and type 1/type 17 responses. Using mice deficient in the CX3CL1 receptor (Cx3cl1GFP/GFP), we demonstrate that CX3CL1 signaling suppresses type 17 and type 2 (IL-4, IL-5, IL-13) responses and associated infiltration of neutrophils and eosinophils. In Cx3cr1GFP/GFP mice we also observed a significant reduction in recently described type 2 interstitial macrophages, a subset of mononuclear phagocytes that robustly express CX3CR1 and fungal pattern recognition receptors (PRRs). These cells also upregulate resistin-like molecule alpha and mannose receptor 1, which have both been shown to contribute to suppression of type 2 immune response. Thus, we postulate that suppression of type 2 interstitial macrophages in Cx3cr1GFP/GFP mice contributes to the exacerbated type 2 responses we observed in our model. Collectively, these data suggest a putative role for both IL-1Ra and CX3CL1 in the suppression of SAFS disease pathology and represent possible therapeutic targets for disease management.

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