Regulation of Immune Responses by Nonhematopoietic Cells in Asthma

Abstract

Nonhematopoietic cells are emerging as important contributors to many inflammatory diseases, including allergic asthma. Recent advances have led to a deeper understanding of how these cells interact with traditional immune cells, thereby modulating their activities in both homeostasis and disease. In addition to their well-established roles in gas exchange and barrier function, lung epithelial cells express an armament of innate sensors that can be triggered by various inhaled environmental agents, leading to the production of proinflammatory molecules. Advances in cell lineage tracing and single-cell RNA sequencing have expanded our knowledge of rare, but immunologically important nonhematopoietic cell populations. In parallel with these advances, novel reverse genetic approaches are revealing how individual genes in different lung-resident nonhematopoietic cell populations contribute to the initiation and maintenance of asthma. This knowledge is already revealing new pathways that can be selectively targeted to treat distinct forms of asthma.

Figure 1:. Asthma Pathobiology

A) The large conducting airways of the lungs branch into terminal alveoli where gas exchange occurs. Airborne environmental agents such as pollutants, allergens, and pathogens interact with the mucosal surfaces of the respiratory tract and contribute to allergic sensitization and asthma exacerbation. B) Asthma is characterized by bronchiolar inflammation, excessive mucus production (indicated by yellow area in the airway lumen), and airway hyperresponsiveness (AHR), which can result in wheezing, coughing, and shortness of breath during exacerbations. C) Asthma encompasses a spectrum of lung pathologies including type 2-high and type-2 low phenotypes characterized by unique profiles of immune cell infiltration, cytokines, and responsiveness to corticosteroid treatment. Type 2-high asthma is mediated by T helper 2 (Th2) cells, eosinophils, and IgE and is generally corticosteroid sensitive. Type 2-low asthma is more heterogenous, severe, corticosteroid resistant, and can include Th17-driven neutrophilic inflammation. Airway-resident immune cells including dendritic cells (DC) and type 2 innate lymphoid cells (ILC2) are important mediators of asthma. Text note: Figures were generated using Servier Medical Art (smart.servier.com) under a Creative Commons Attribution 3.0 Unported License.

Figure 2:. Nonhematopoietic Cells in Asthma

A) Nonhematopoietic airway cells include fibroblasts and several types of ECs: basal cells, secretory cells (club and goblet cells), ciliated cells, and solitary chemosensory cells such as brush cells that can accumulate during pathological conditions. B) Airway-resident nonhematopoietic cells contribute to inflammation in asthma via multiple mechanisms including: autocrine/paracrine signaling among different cells, ultimately leading to leukocyte recruitment. Cytokine signals from nonhematopoietic cells also affect interactions among immune cells by influencing the activation status of DCs and ILC2s. C) Nonhematopoietic cell-immune cell interactions involve multiple mechanisms of communication, including secretion of soluble factors such as cytokines and EVs carrying cargo that includes enzymes, microRNAs, and pro-inflammatory prostaglandins. Direct interactions between cells also occurs, including gap junction-mediated contact between ECs and alveolar macrophages, efferocytosis of dead ECs by neighboring ECs, and MHC-II-mediated antigen presentation by ECs. Text note: Figures were generated using Servier Medical Art (smart.servier.com) under a Creative Commons Attribution 3.0 Unported License.