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Logo of nihpaAbout Author manuscriptsSubmit a manuscriptHHS Public Access; Author Manuscript; Accepted for publication in peer reviewed journal;
Nat Med. Author manuscript; available in PMC 2011 November 1.
Published in final edited form as:
PMCID: PMC3170000

Shedding LIGHT on severe asthma


Moderate to severe asthma is difficult to treat because recurring bouts of inflammation in the lungs induce fibrosis, which reduces lung elasticity, gas exchange and responses to conventional therapy. A recent study identifies the tumor necrosis factor family member LIGHT as an essential mediator of airway fibrosis in a mouse model of chronic asthma (pages 596–603).

The majority of asthma cases can be effectively managed with a combination of inhaled medications. Corticosteroids, which are slow-acting anti-inflammatory drugs, reduce the frequency and severity of asthma attacks, and faster-acting bronchodilators relax airway smooth muscles. However, these treatments are much less effective in the 5–10% of people who suffer from severe asthma1. These individuals typically have more frequent attacks and are at an increased risk of dying during an attack, because their airways have permanently narrowed as a result of chronic inflammation and its associated scarring (lung remodeling). Although asthma mortality rates are typically low, severe asthma attacks can result in death by suffocation. Indeed, there are approximately 4,200 asthma-related deaths each year in the US alone2, thus emphasizing the need for more aggressive treatment strategies that can decrease the progression of lung remodeling in asthma.

Asthma is associated with a T cell–mediated immune response and is typically regarded as a T helper 2 type 2 (TH2) disorder. CD4+ TH2 cells produce the cytokines interleukin-4 (IL-4), IL-5 and IL-13, which participate in the recruitment of eosinophils, one of the dominant inflammatory cell types in the airways of people with asthma. However, as the disease advances and becomes chronic, it can adopt additional characteristics that include corticosteroid refractoriness and neutrophilic inflammation. When this happens, TH1 and TH17 responses emerge, which are defined by the production of interferon-γ and IL-17, respectively. These cytokines show strong proinflammatory activity and participate in neutrophil recruitment. Thus, it has been hypothesized that when asthma progresses from a mild to a severe form of the disease, the immune response switches to a mixed cytokine response involving TH2, TH1 and TH17 cells. At this stage, increases in the production of tumor necrosis factor-α (TNF-α), lymphotoxin and other TNF family members are also commonly seen3.

In this issue of Nature Medicine, Doherty et al.4 identify the TNF family member LIGHT (lymphotoxin-related inducible ligand that competes for glycoprotein D binding to herpesvirus entry mediator on T cells; also known as TNFSF14) as a crucial regulator of airway remodeling in mouse models of chronic asthma. They show that blockade or absence of LIGHT reduced subepithelial fibrosis, smooth muscle hypertrophy and hyperplasia, and airway hyper-responsiveness after allergen challenge but did not affect airway eosinophilia4. The authors also show that the production of the profibrotic cytokines transforming growth factor-β (TGF-β) and IL-13 by macrophages and eosinophils, respectively, is important in LIGHT-induced remodeling4. These results suggest that LIGHT could be targeted to treat airway remodeling in asthma. This is noteworthy because there are currently no drugs available that specifically target the mechanisms of asthmatic lung remodeling.

LIGHT is a membrane-expressed protein related to the membrane form of lymphotoxin (LTαβ)5. Both proteins are expressed in various tissues, with the greatest expression found in the lung, spleen and thymus. LIGHT binds the herpesvirus entry mediator (HVEM) and competes with LTαβ for binding to the lymphotoxin β receptor (LTβR)5,6. LIGHT was originally characterized as a co-stimulatory factor on lymphoid cells and as an inhibitor of herpesvirus infection68; however, it has also been shown to increase the severity of various T cell–mediated diseases8,9.

Because other TNF family members have been shown to be involved in the pathogenesis of asthmatic inflammation3, Doherty et al.4 examined whether the development of allergen-induced asthma is regulated by LIGHT. Using a soluble inhibitor of LIGHT (a fusion protein of LTβR) or LIGHT-deficient mice, they showed that development of peribronchial fibrosis and smooth muscle hypertrophy was markedly reduced in the absence of LIGHT after chronic exposure to house dust mite allergen or to ovalbumin, a model allergen. The decrease in lung remodeling was also associated with a marked reduction in airway hyperresponsiveness, suggesting an overall improvement in airway physiology in the absence of LIGHT.

Notably, production of the profibrotic cytokine TGF-β, which is known to stimulate extracellular matrix production by fibroblasts10, was significantly reduced in allergen- challenged LIGHT-deficient mice. Agonists of LTβR signaling were also shown to induce TGF-β–dependent peribronchial fibrosis. The authors identified LTβR-expressing macrophages located in the subepithelial region of the lung as the primary producers of TGF-β in their model system. Because TGF-β–producing macrophages have been implicated in the pathogenesis of a number of lung remodeling diseases, including chronic obstructive pulmonary disease, asthma and hypersensitivity pneumonitis11, they concluded that controlling the number of TGF-β–producing lung macrophages might be, at least in part, how LIGHT stimulates subepithelial fibrosis in asthma.

Eosinophils have also been implicated in the development of subepithelial fibrosis in asthma, largely because they are important producers of the profibrotic cytokine IL-13 (ref. 12). Like TGF-β, IL-13 is an important mediator of lung remodeling, and expression of IL-13 is elevated in the lungs of people with evidence of asthmatic remodeling13. TGF-β and IL-13 have also been shown to synergistically increase the development of pulmonary fibrosis11. Doherty et al.4 observed a marked reduction in IL-13 expression in the lungs of allergen-challenged LIGHT-deficient mice. Notably, they observed no reduction in TH2 cell differentiation or recruitment, thereby suggesting that the impaired IL-13 response in Tnfsf14−/− mice might be attributed to another cell type.

The authors then identified eosinophils as the likely culprit, as these cells had high intra-cellular expression of IL-13 in mice that had been subjected to the chronic asthma protocol4. They found that eosinophils expressed HVEM, and recombinant LIGHT treatment of cultured eosinophils from antigen-sensitized mice triggered IL-13 production, presumably by LIGHT binding to HVEM. Thus, the studies of Doherty et al.4 show that LIGHT-LTβR or LIGHT-HVEM interactions promote lung remodeling in asthma by simultaneously increasing TGF-β production by macrophages and IL-13 expression in eosinophils. Moreover, both of these mechanisms have been implicated in asthmatic airway remodeling in humans12.

TNF family members have been identified as therapeutic targets in a variety of chronic inflammatory diseases, including rheumatoid arthritis and Crohn’s disease14. Similarly to LIGHT, TNF-α has been implicated in asthma pathogenesis. This factor upregulates adhesion molecules, facilitates the migration of inflammatory neutrophils and eosinophils (Fig. 1), and activates profibrotic mechanisms in the airway. Recombinant TNF-α has also been shown to directly increase airway hyper-reactivity3. Production of TNF-α and LIGHT in the lung also correlates with decreased lung function in people with asthma, suggesting a possible role for both TNF-α and LIGHT in the pathogenesis of severe asthma14. Thus, LIGHT could represent a new target for therapy of asthma-related airway remodeling.

Figure 1
Direct and indirect effects of LIGHT signaling in chronic asthma. Doherty et al.4 show that the TNF family member LIGHT, which is expressed by activated B and T lymphocytes, can bind and signal through HVEM or LTβR, which is expressed on many ...

Given that TNF-α, LIGHT and LTαβ have all been linked to airway remodeling in asthma, it is necessary to better understand how these proteins are regulated at various stages of the disease. The major cell types that produce TNF-α, LTαβ and LIGHT also remain unclear. Because LIGHT and LTαβ are expressed on the cell surface, it will be crucial to understand whether they require direct cell-to-cell contact or whether they must be shed or cleaved before engaging their receptors. Also, because herpes simplex virus establishes infection by binding to HVEM, it will be interesting to determine whether recurrent HSV infection and HVEM engagement predisposes individuals to pulmonary fibrosis.

Although Doherty et al.4 showed that LIGHT directly upregulated the production of TGF-β1 in macrophages and IL-13 production in eosinophils, IL-13 blocking and cell depletion studies were not done to definitively prove that LIGHT-induced remodeling is dependent on IL-13, macrophages and eosinophils. Finally, if LIGHT is to be developed as a treatment for asthma-related remodeling, future research should focus on determining whether anti-LIGHT therapeutics can slow or reverse the progression of established airway disease.



The authors declare no competing financial interests.


1. Barnes PJ. Nat Rev Immunol. 2008;8:183–192. [PubMed]
2. Moorman JE, et al. MMWR Surveill Summ. 2007;56:1–54. [PubMed]
3. Berry MA, et al. N Engl J Med. 2006;354:697–708. [PubMed]
4. Doherty TA, et al. Nat Med. 2011;17:596–603. [PMC free article] [PubMed]
5. Mauri DN, et al. Immunity. 1998;8:21–30. [PubMed]
6. Scheu S, et al. J Exp Med. 2002;195:1613–1624. [PMC free article] [PubMed]
7. Tamada K, et al. Nat Med. 2000;6:283–289. [PubMed]
8. Wang J, et al. J Clin Invest. 2001;108:1771–1780. [PMC free article] [PubMed]
9. Shaikh RB, et al. J Immunol. 2001;167:6330–6337. [PubMed]
10. Minshall EM, et al. Am J Respir Cell Mol Biol. 1997;17:326–333. [PubMed]
11. de Boer WI, et al. Am J Respir Crit Care Med. 1998;158:1951–1957. [PubMed]
12. Wilson MS, Wynn TA. Mucosal Immunol. 2009;2:103–121. [PMC free article] [PubMed]
13. Woodruff PG, et al. Am J Respir Crit Care Med. 2009;180:388–395. [PMC free article] [PubMed]
14. Ware CF. Annu Rev Immunol. 2005;23:787–819. [PubMed]