An Outside-In View of the Beneficial and Detrimental Impact of Type-2 Inflammation in the Lung

Bacterial and viral infections initiate classical type-1 immune responses. Together, pathogen-specific CD8+ cytotoxic T cells, CD4+ T helper 1 (Th1) cells, and classically activated macrophages cooperate to kill and eliminate infected cells. After pathogen clearance, the type-1 response resolves. Resolution of a classical inflammatory response is critical to host health. The importance of limiting inflammation after pathogen clearance is evident from the association of chronic type-1 inflammation with diverse diseases ranging from inflammatory bowel disease, chronic obstructive pulmonary disease, diabetes, and Alzheimer's disease [1-4].

While optimal for protection against viruses and bacteria, type-1 inflammation is not effective at controlling large extracellular helminths. These worms are orders of magnitude larger than viruses and bacteria, preventing classical macrophage clearance and phagocytosis of infected cells. If such a response was mounted, the inability of the host to clear the worms would lead to persistent type-1 inflammation. As stated above, such persistence of type-1 inflammation would ultimately be detrimental to the host. To avoid this, mammals have evolved the ability to mount a type-2 immune response to combat extracellular worm infections [5, 6]. Unlike type-1-driven immunity, which is focused on the direct killing and clearance of infected cells, type-2 inflammation is centered on the recruitment of innate immune cells to the site of infection; limiting nutrient availability during feeding by walling off the attachment site (wound healing response); and clearing of the worm through mucus production and smooth muscle contraction (weep and sweep). Also important, type-2 inflammation suppresses classical type-1 inflammation. These processes occur in multiple tissues infected by these parasites including the lung.

However, type-2 inflammation can also be detrimental to the host. If a type-2 response is evoked in the presence of a normally inert protein (allergen), it can be associated with allergic disease. In the context of the lung, type-2 inflammation to allergens is defined as allergic asthma [7]. Interestingly, the pathobiology associated with soil-transmitted helminth infection, as they migrate through the lung, closely resembles the pathobiology seen in the lungs of asthmatics. In both cases, the classical hallmarks of type-2 inflammation are evident: eosinophilia, goblet cell hyperplasia and mucus production, and elevated immunoglobulin-E, IgG1, and IgG4.

These classical hallmarks of type-2 inflammation are driven in large part by the production of type-2 cytokines—interleukin-4, IL-5, and IL-13 [8]. IL-4 is critical for the class-switching of B cells to IgE and IgG1. IL-5 mobilizes eosinophils from the bone marrow. IL-13 drives both the induction of goblet cell hyperplasia and mucus production as well as smooth muscle contractility. The critical nature of these cytokines in driving type-2 inflammation is illustrated by the success of biologics targeting them and their receptors for the treatment of allergic disease [9, 10].

This review volume is focused on the factors initiating type-2 inflammation in the lung, the innate and adaptive immune cells producing type-2 cytokines, and how immune cells and their soluble products interact with their environment to drive airway disease (Figure 1). Importantly, the volume also delves into how lung architecture impacts immune-stromal cross-talk. Specific focus is given to how immune cells and their products influence smooth muscle, neurons, and epithelium to impact disease severity and the underlying pathobiology of pulmonary disease.

The volume starts by addressing how early-life exposures and the microbiome can impact asthma onset in later life (Harris and Sperling) [11, 12]. Harris and colleagues review the relationship between intestinal, lung, and skin microbiota and their differential impact on allergic disease [11]. How early-life alterations of the microbiota impact asthma risk are also discussed. Together, these findings support an important role for the gut–lung axis in modulating disease susceptibility.

This review is complemented by Sperling and colleagues who, through a lens of their own seminal work, introduce the new concept of “Farm-Friends” [12]. Farm-Friends are microbes associated with farming that work to suppress asthma. The review investigates potential mechanisms for how early-life exposures to Farm-Friends can limit allergic disease incidence and how gained insights might be leveraged therapeutically.

The third microbiota focused review details how multi-omic approaches are shedding light on how the human microbiome impacts allergic airway disease heterogeneity [13]. Importantly, Dr. Huang interrogates how different omic-based approaches are being used in “bedside-to-bench investigations” to reveal links between the microbiome, the immune system, and asthma outcomes in patients.

The next review by Lloyd and colleagues touches on the important but often overlooked role that lung architecture has on airway inflammation [14]. While immunologists now appreciate that secondary lymphoid organs are not just bags of cells, a similar mindset regarding nonlymphoid organs is also likely key to understanding how type-2 inflammation impacts lung disease. Using their own work as a guide, this review highlights how a deeper understanding of lung architecture, the airway stroma, and “spatial responses” can be the basis for more effective therapies for asthma patients.

The review volume then turns its focus to the various immune cells associated with asthma and type-2 inflammation. First, it takes a look at how new ground-breaking models of human asthma are reshaping the way the field thinks about the disease [15]. Using such models helps to reveal how immune-epithelial cell circuits behave in humans. This is likely critical to our eventual understanding of the diverse pathobiology and endotypes observed in human asthma.

The next review takes an in-depth look at the role and regulation of mast cells, basophils, and eosinophils in asthma [16, 17]. Gauvreau and colleagues discuss how eosinophils and their progenitors impact allergic inflammation [16]. With this in mind, the authors explore how standard therapies used more broadly to treat pulmonary diseases associated with eosinophilia compare to newer, more targeted approaches. Next, Huang and colleagues drill down into the inner workings of mast cells to reveal how transcriptional regulation drives mast cell development and differentiation [17]. This is followed by a thorough look into the role that human mast cells play in allergic airway disease.

The last review centered on innate immune cells explores how the timing, location, and heterogeneity of pulmonary group 2 innate lymphoid cell (ILC2) responses can differentially impact pulmonary disease (infection, asthma, and COPD) [18]. Verma et al. place particular focus on the different roles that circulating and lung-resident ILC2 serve in maintaining barrier immunity and the implications this has with respect to the gut–lung axis.

Pivoting from the innate immune system, the next set of reviews delve into the role of the adaptive immune system in allergic airways disease. Rahimi and colleagues look specifically at the development, activation, and role of tissue-resident CD4+ Th2 cells in chronic airway disease [19]. Of note, the review emphasizes how targeting these cells, which are uniquely positioned in the airways to rapidly respond to allergens, might have significant therapeutic benefit for asthma patients. In a similar vein, Stadhouders and colleagues focus on Tc2 cells and how these often overlooked type-2 cytokine producing CD8+ T cells are gaining attention as important players in steroid-resistant, severe asthma [20]. The role of Tc2 is compared and contrasted against non-T2 T cells and ILC2.

The next review continues on the theme of T cells in severe asthma by focusing on the complex relationship between type-2 and non-type-2 immunity in asthma [21]. This review highlights that both Type-1 (T1) and Type-2 (T2) immune cells are often present in the lungs of the most difficult to treat asthmatics. While corticosteroids may be effective against the T2 arm in such patients with a mixed T1/T2 endotype, these drugs are less effective at controlling T1-mediated inflammation. As such, therapies designed to treat severe asthma may need to cater to targeting both immune arms in order to achieve high efficacy.

Peebles and colleagues also look at lung endotypes, but in this case in the setting of cystic fibrosis [22]. Led by their own seminal work in the field, this review details the presence of a T2 endotype in CF. Importantly, the data provided indicate that this T2 endotype appears to be increased in the absence of functional CFTR and involves both ILC2 and CD4+ Th2 cells.

Next, Wang and colleagues shift the adaptive immune focus from T cells to products of B cells [23]. Here the authors detail how immunoglobulin G (IgG) has anti-inflammatory properties through binding of Fc receptors on immune cells. This suppressive effect is due to a specific glycosylation on IgG—sialyation. Importantly, new work by their group shows that the suppressive effect of sialyated antibodies works in part through the repression of NFkB. The specific impact of sialyated IgG on pulmonary inflammation is also reviewed.

Continuing to look at how soluble factors influence pulmonary disease, the next two reviews investigate the role of cytokines in the lung. In the first review, Madala and colleagues take a general look at the various impacts that cytokines and the cells that produce them have on the remodeling of the lung in settings of inflammation [24]. The next review focuses specifically on how cytokines regulate airway smooth muscle (ASM) function [25]. Interestingly, Ford et al. discuss how canonical T1 and T2 cytokines modulate ASM function and how they may differentially influence asthma outcomes. In addition to cytokines, the review also looks at the impact that corticosteroids and long-acting β2-adrenergic receptor agonists have on ASM in asthma.

The volume wraps up by looking at the emerging field of neuroimmunology and the long-studied arena of mucin biology [26, 27]. The review by Drake and colleagues provides a detailed look at how immune–nerve interactions regulate healthy lung function [26]. They contrast this with how disruption of these interactions can lead to airway disease. Similarly, the review by Ye et al. [27] gives us an in-depth look at how different mucins are produced and regulated in both the healthy and asthmatic lungs. This review touches on how restoring normal mucus production in asthmatics could be key to treating disease.

In sum, these reviews help to establish a link between the gut–lung axis and how environmental exposures and alterations in the microbiota impact asthma susceptibility. In addition, the volume highlights the importance of understanding how lung architecture influences immune–stromal interactions (ASM, airway epithelium, neurons, and goblet cells). In doing so, we gain valuable insights into the pathobiology of asthma. Lastly, by considering how mucins, cytokines, and antibodies differentially promote and suppress allergic inflammation and airway disease, we can better design therapeutics and interventions to do the same.

The author declares no conflicts of interest.