Fungal-mediated lung allergic airway disease: The critical role of macrophages and dendritic cells

Abstract

Fungi are abundant in the environment, causing our lungs to be constantly exposed to a diverse range of species. While the majority of these are cleared effectively in healthy individuals, constant exposure to spores (especially Aspergillus spp.) can lead to the development of allergic inflammation that underpins and worsen diseases such as asthma. Despite this, the precise mechanisms that underpin the development of fungal allergic disease are poorly understood. Innate immune cells, such as macrophages (MΦs) and dendritic cells (DCs), have been shown to be critical for mediating allergic inflammation to a range of different allergens. This review will focus on the crucial role of MΦ and DCs in mediating antifungal immunity, evaluating how these immune cells mediate allergic inflammation within the context of the lung environment. Ultimately, we aim to highlight important future research questions that will lead to novel therapeutic strategies for fungal allergic diseases.

Fig 1. The influence of the lung environment and fungal spores on MΦ responses during allergic inflammation.

In a “healthy lung environment” (left), (1) the majority of inhaled fungal spores are rapidly removed from the airways by AlvMΦ [43]. (2) Some AlvMΦ may not acquire spores and generate an anti-inflammatory environment [54]. (3) Spore uptake and killing, facilitated by the aid of components of the lung environment including epithelial cell secreted surfactants (SP-A, SP-D) and mucus (particularly the mucin glycoproteins, e.g., Muc5b) [45,159]. (4) Other features of the airway include a low nutrient airway environment (maintained by airway epithelial active transporters [170]) that maintain an immunoregulatory MΦ environment [144]. Upon allergic inflammation (right), (5) repeat spore exposure causes apoptosis or necrosis of resident AlvMΦ [183]. These are replaced by inflammatory IntMΦs [26] or recruited monocytes [37,76]. Both express altered inflammatory transcriptional and epigenetic profiles, leading to differential inflammatory responses upon subsequent spore exposure [71,73]. (6) Epithelial cell sensing of fungal material and/or damage to epithelial cell barrier (via fungal proteases), triggers the release of “alarmins” (e.g., TSLP, IL-33, IL-6, IL-22, and CCL2) [–175]. (7) These epithelial signals can recruit and activate other immune cells such as mast cells, basophils and ILC2s inducing a type 2 cytokine environment directly impacting MΦ responses (potentially reducing spore killing) [–138]. (8) Persistence of spores, disrupted epithelial barrier, immune cell infiltration (including CD4⁺ T cells) leads to a type 2 and 17 cytokine environment, alteration of airway nutrient concentrations and hyper secretion of mucus (including Muc5ac) and surfactants [151,158]. These further promote pro-inflammatory MΦ antifungal responses, possibly sustaining allergic inflammation. Figures were created with BioRender.com. AlvMΦ, alveolar macrophage; CCL, chemokine ligand; DAMP, damage-associated molecular pattern; IL, interleukin; IntMΦ, interstitial macrophage; ILC, innate lymphoid cell; MΦ, macrophage; SP, surfactant protein; TSLP, thymic stromal lymphopoietin.

Fig 2. Understanding how DC induction of fungal allergic inflammation is shaped by the lung environment.

In health (left), DCs predominantly reside in the tissue but can project dendrites into the airway to sample antigen. (1) As AlvMΦs predominantly clear inhaled spores [43], exposure of DCs to fungal antigen is minimal reducing potential for inflammatory responses. (2) DC subsets, especially cDC1s, assume housekeeping duties (e.g., clearance of apoptotic cells) maintaining a tolerogenic phenotype. (3) Upon migration to draining LN lung DCs, in concert with other subsets such as pDCs, induce T-reg generation further maintaining an immuno-regulatory lung environment. (4) Fungal allergic inflammation is initiated upon cDC2 acquisition of Af spores and migration to the draining LN where they can prime adaptive CD4⁺ T cell responses (right). (5) While the precise mechanisms by which cDC2 mediate these responses to spores is unclear, the lung environment is known to directly influence this process. Fungal secretory products (including proteases) in the airway lumen can not only activate DCs directly, but also damage the epithelial barrier. This allows spores to move beyond the epithelial barrier and potentially activate cDC2s in the deeper underlying tissue. Furthermore, epithelial cell responses to fungi and/or barrier damage triggers the release of alarmins, chemokines, cytokines, and DAMPs (e.g., CCL2, IL-6, IL-33, and TSLP^173, [174,175]), which can further activate DCs to promote allergic response. In addition, ILCs and mast cells (which can be activated by epithelial signals) further promote type 2 and type 17 cytokine which further conditions DCs to exacerbate allergic inflammation [68,145,180,184]. Other lung environmental factors such as altered nutrient availability and increased surfactant/ mucus concentrations [45,158] can further shape DC responses. (6) These features can lead to the formation of several inflammatory DC states (infDC1, infDC2, and infDC3) and possibly DCs differentiated from monocytes (moDCs) which further amplify and sustain fungal allergic inflammatory disease. Figures were created with BioRender.com. AlvMΦ, alveolar macrophage; CCL, chemokine ligand; DC, dendritic cell; IL, interleukin; moDC, monocyte-derived dendritic cell TSLP, thymic stromal lymphopoietin.