The balance between immunity and inflammation

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Science  08 Sep 2017:
Vol. 357, Issue 6355, pp. 973-974
DOI: 10.1126/science.aao3086

Lungs execute two critical functions that can be at odds with one another: eliminating harmful toxins, particulates, and microbes; and exchanging gas through uninflamed structures—alveoli—to collect oxygen and discharge carbon dioxide. Lungs have a multilayered response to unwanted invaders, offering physical barriers as well as arranging immune cells at airway surfaces. Yet, lungs have the “Goldilocks” challenge of deploying this armory with just the right amount of inflammation. Consequently, lung immunity must be choreographed so that invaders are purged quickly, inflammation tempered, and homeostasis preserved. In this issue, two papers reveal how lung immunity handles these tasks and what happens when things go awry. Shlezinger et al. (1) on page 1037 unveil a clever trick that neutrophils play on inhaled fungal spores to resist life-threatening infections. This may reveal new treatment strategies. On page 1014, Sinclair et al. (2) report metabolic derangements in dendritic cells (DCs) that reprogram the allergic response to inhaled particulates, with implications for asthma.

The balance of lung immunity

Lung immunity faces the “Goldilocks” challenge of responding with just the right amount of inflammation.


In urban and rural air, 4 to 11% of the fine particle mass contains fungal spores (3). More than 300 million people suffer serious fungal-related diseases that kill more than 1.6 million people annually (4). More than 1 million fungal species populate our planet, and 300 are human pathogens (5). Aspergillus is a common cause of systemic infection in people with impaired immunity owing to AIDS, complications associated with chemotherapy, or treatments for inflammatory disorders, often with high fatality rates.

Shlezinger et al. studied the spores (conidia) from Aspergillus fumigatus. Every day, humans each inhale 103 to 1010 of these seemingly innocuous airborne conidia. In addition to being a common aeroallergen, A. fumigatus infection causes >200,000 cases of invasive aspergillosis annually, which is associated with mortality rates of up to 90% in some patients with impaired immunity (6). Shlezinger et al. report a mechanism of mammalian innate immunity to inhaled A. fumigatus conidia. They show how neutrophils (a type of innate immune cell) kill A. fumigatus conidia and, conversely, how the fungus resists this process. They did this using fluorescent Aspergillus reporter (FLARE)—A. fumigatus conidia that “report” through fluorescence viability on contact with leukocytes in vivo (7). Neutrophils induce caspase-dependent programmed cell death (PCD) in the conidia, triggered by host oxygen-dependent signals—e.g., reduced form of nicotinamide adenine dinucleotide phosphate (NADPH) in neutrophils (see the figure). Conversely, to counteract PCD, A. fumigatus conidia use AfBir1, a gene homologous to human survivin, which encodes a BIR domain and suppresses PCD. Targeting AfBir1 with a chemical inhibitor augments fungal PCD and host survival. Thus, AfBir1 may be an appealing drug target.

Control of PCD is central to all types of host-pathogen interactions. For example, PCD occurs in plant fungal pathogens (8). PCD is a response to noxious stimuli (9); fungitoxic plant-defense products also trigger fungal PCD (8, 9). Thus, while interacting with host cells, fungi are exposed to host-derived PCD-inducing molecules. Genetic manipulation of the fungal anti-PCD response by ablating Bir1 reduces fungal virulence (10). Thus, fungal PCD is triggered and regulated by Bir1 during interaction with plants and mammals. Because human (and mouse) neutrophils trigger PCD in A. fumigatus conidia, targeting AfBir1 could be used to bolster innate immunity or undermine fungal immune evasion. The arsenal of antifungal drugs is small and dwindling. Multidrug resistance is now a global threat, so new drugs are needed.

Although neutrophils are potent killers of fungi, this cell type exemplifies the two sides of leukocyte function. An example is their pathological role in a severe form of allergic inflammation, neutrophilic asthma. Asthma afflicts hundreds of millions of people globally. In 2007, medical expenses from asthma cost the United States $50.1 billion (11).

Asthma often originates from the inhalation of innocuous substances or mild irritants that elicit a disproportionately potent immune response in the lungs. This allergic response is often characterized by an excessive influx of eosinophils (granulocytic immune cells) into the lungs. Whereas neutrophilic asthma results from the accumulation of neutrophils, also a granulocytic immune cell. Interestingly, these dichotomous granulocyte immune cell responses are reciprocally regulated by discrete populations of T helper cells (12). DCs are central mediators of immunity and inflammation. Although lymphocytes (e.g., T cells) are directly responsible for positioning granulocytes at sites of insult, T helper cells first require interaction with DCs. Drawing from environmental cues, DCs imprint T helper cells with defined functions. For example, this can promote differentiation of T helper cells that recruit neutrophils or eosinophils to the lungs. How do DCs regulate an eosinophil-inducing versus a neutrophil-inducing T helper cell response?

Sinclair et al. offer a compelling model whereby cell-intrinsic metabolism regulates the tissue distribution of DCs and controls T helper cell fate determination. Using a mouse model of allergic asthma, the authors found that mice with a conditional deletion of mechanistic target of rapamycin (Mtor, a central regulator of metabolism) in DCs no longer experienced eosinophilic asthma upon allergen inhalation. Rather, large numbers of neutrophils were recruited to the lungs. These striking findings may help resolve several disjointed clinical and epidemiologic observations. Individuals with metabolic syndrome, denoted by obesity and deficits in fasting glucose metabolism, experience increased rates of asthma (13). Moreover, asthma associated with obesity is typically neutrophilic (14). It is possible that the irregularities in glucose metabolism that are evident in obese individuals lead to reduced mTOR activation and the skewing of neutrophil-inducing T helper cells in response to aeroallergens. Thus, therapies that restore glucose metabolism in pulmonary DCs could provide new treatment options for neutrophilic asthma.

These findings underline the balance between helpful lung immunity and harmful inflammation. They disclose new mechanisms as well as host and pathogen targets that offer prospective arrows in the quiver of our therapeutic arsenal.


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