Role of Il-13 in Asthma
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Asthma is an inflammatory response triggered by endogenous or exogenous antigens. Asthma is associated with increased mucous production and bronchial epithelium changes which ultimately leads to an obstruction of the airways (Schuijs, Willart, Hammad, & Lambrecht, 2013, p. 351) . The inflammatory response is elicited by T helper cells, specifically T-helper 2 cells (TH2), which releases interleukins (IL)-4, 5, and 13 and these play a vital role in the severity of the condition (Woodruff et al., 2009, p. 388). Although IL-4 and 5 play important roles in asthmatic inflammation, only IL-13 will be discussed in this paper. IL-13 is released by both the innate and adaptive immune cells; it can act on smooth muscles, alveolar macrophages, and may contribute to production of reactive oxygen species (ROS) (De Boever et al., 2014, p. 1; Woodruff et al., 2009, p. 388). There are two types of alveolar macrophage M1 and M2, M1s respond to endogenous antigens, such as opportunistic pathogens, while M2s respond to exogenous antigens, such as pollen (Balhara & Gounni, 2012, p. 606). Alveolar macrophages (M2s) differentiate from monocytes when IL-13 mediators are released locally into the lungs (Balhara & Gounni, 2012, pp. 605-606) . After being primarily activated by IL-13, alveolar macrophages have prominent roles in causing the inflammatory onset, they phagocytose antigens, indirectly promote airway destruction by releasing ROS and might be responsible in initiating repair (Fitzpatrick, Holguin, Teague, & Brown, 2008, p. 1377; Martinez-Nunez, Louafi, & Sanchez-Elsner, 2011, p. 1786) . IL-13 may be the main mediator responsible for regulating the activity of alveolar macrophages (M2) and it is important to note that alveolar macrophages must receive signals from ILs in order to become activated (Martinez-Nunez et al., 2011, pp. 1786-1787; Ramalingam et al., 2008, p. 25). IL-13 has a specific IL receptor (IL-13Ra1) on the surface of macrophages, fibroblasts and on bronchial epithelial cells; this receptor can be inhibited by therapeutic drugs and by endogenous micro-RNAs (Martinez-Nunez et al., 2011, p. 1787; Ramalingam et al., 2008, p. 25). In animal models the knockout of IL-13Ra1 causes asthma related inflammation to decline, thus providing evidence for the importance of IL-13 in the pathogenesis of asthma (Martinez-Nunez et al., 2011, p. 1786).
IL-13 role on alveolar macrophages and fibroblasts
Alveolar macrophages are the first cells to be activated by IL-13 when an antigen invades the respiratory tract, followed by neutrophils, and leukocytes (Fulkerson, Fischetti, Hassman, Nikolaidis, & Rothenberg, 2006, p. 339) Similarly it is noted that eosinophils are also recruited by IL-13 and this may have a significant role in prolonged inflammation (Fulkerson et al., 2006, p. 339). Studies using IL-13Ra1 knockout mice noticed an increased intrusions of macrophages and decreased eosinophils within the lung airways, this suggest that macrophages do not always need receptor activation and may be activating through an unknown induction mechanism influenced by IL-13 (Ramalingam et al., 2008, p. 29). As it will be noted in the next section, the results from Ramalingam et al. (2008) study may help to explain why IL-13 isn’t needed to maintain a prolonged inflammatory response by alvelolar macrophages, instead this study suggest that a prolonged response may be due to eosinophil recruitment (pp.29-31). Even though TH2 levels were high, the fibroblast response depleted in the IL-13Ra1 knockout mice, thus suggesting that IL-13 is an important factor in the repair process, more so than it is in the inflammatory maintenance response (Ramalingam et al., 2008, pp. 26, 31).
IL-13 initiates the inflammatory response, but isn’t needed to maintain/prolong response
Studies using transgenic mice models have revealed a prominent role of IL-13 in inducing macrophages, neutrophils, eosinophils and lymphocytes (Fulkerson et al., 2006, p. 339). Because asthma depletes the respiratory airway function, continuous inflammatory events caused by IL-13 can lead to irreversible damages to the airway and thus may lead to chronic asthma (Fulkerson et al., 2006, p. 337). A study conducted by Fulkerson et al. (2006) used transgenic mice to control the gene expression of IL-13 through the use of an inducer doxycycline (p. 337). Doxycyline functions by allowing overexpression of the IL-13 gene; by overexpressing researchers wanted to determine the longterm role of IL-13 on immune cells and the respiratory repair process via fibroblasts (Fulkerson et al., 2006, p. 337). When transgenic mice were administered Doxycyline for a week there was a large increase in immune cells within the lung fluid compared to non-transgenic mice under similar conditions (Fulkerson et al., 2006, p. 339). As the Doxycycline therapy ended, IL-13 levels depleted, the immune cell accumulation remained prominent for 2 more weeks, this suggests that even after IL-13 removal, the immune cells, mostly alvelolar macrophages and eosinophils, are still active within the lung tissues (Fulkerson et al., 2006, pp. 339-344). A Similar study used mice models and induced them with a known asthmatic antigen, and a known anti-inflammatory (Liu et al., 2013, p. 788). The extraction of lung fluid after treatments with the antigen and anti-inflammatory revealed that TH2, IL-13 and immune cells counts had depleted significantly in a short period of time, in contrast, mice not treated with the anti-inflammatory had high initial levels of IL-13 and depleted over a short time period, but immune cell counts remained high (Liu et al., 2013, p. 789). This provides further evidence that IL-13 does not have a prominent role in extending the inflammatory response, but only “kick starts” the process, thus there may be another mechanism that causes prolonged immune cell responses to which further studies are needed.
Remodelling of bronchiole tissues is mediated by IL-13, but is patient specific
After immune cell infiltration significant damage is caused by alvelolar macrophages to the lung tissues and for this reason remodelling of the airways must take place (Fulkerson et al., 2006, p. 340). Not surprisingly, IL-13 induces cartilage production via fibroblast induction, but the cartilage isn’t always distributed in a well-structured manner, instead it is laid down randomly (Fulkerson et al., 2006, p. 340). This assists in causing is emphysema where large airways form and lung function depletes; of note emphysema is also relatively caused by immune cell destruction of lung tissues by ROS (Fulkerson et al., 2006, p. 340). Scarring takes place in order to repair the damaged alveolar tissues, but this doesn’t restore the tissues back to normal because significant loss has already occurred due to IL-13 mediated responses (Fulkerson et al., 2006, p. 345). A protective coating of mucus results due to a damaged airway.
A large increase in mucus and collagen production occurred in histological samples of alvelolar tissues in mice treated with antigens (Liu et al., 2013, p. 789). It is evident that IL-13 causes increased sections of mucus, and notably this response continues even after IL-13 has been removed (Fulkerson et al., 2006, p. 340). Just like in mice models, thick mucus production was noted in asthmatic patients (Woodruff et al., 2009, p. 391). Woodruff et al. (2009) found that IL-13 levels in human lung tissues positively correlated with TH2 levels (pp. 390-391). More importantly they determined that remodelling was taking place at a faster rate in asthmatic patients with higher levels of TH2 and IL-13 compared to patients with lower levels and non-asthmatic patients (Woodruff et al., 2009, p. 391). This was confirmed by taking samples of bronchiole tissues and histologically viewing the thicker basement membranes of patients with higher levels of mediators (Woodruff et al., 2009, p. 391). Although the findings above seem to correlate with various other studies, the conclusion was that different patients have different amounts of IL-13 and TH2 released and for this reason not all asthmatic patients have the same inflammatory effects (Woodruff et al., 2009, pp. 392-393). This may also explain the reason why treatments are not effective in all asthmatic patients; it could be due to decreased IL-13 gene regulation and/or a resistance to treatments, for this reason more insight is needed into why IL-13 and TH2 levels are not the same in all asthmatic patients (Woodruff et al., 2009, pp. 392-393). This could potentially aid in finding patient specific treatments which may prevent untreated/wrongfully treated asthma complication later in life.
Treatments must be patient specific for IL-13 related asthma
Biomarker Periostin, is produced when a gene located in the bronchial cells is activated by IL-13 (Jia et al., 2012, p. 652). It is heavily expressed in patients who have eosinophilic asthma, large amounts of mucus and substantial remodelling of lungs tissues (Jia et al., 2012, p. 648). Studies have indicated that therapeutic drugs are effective when periostin levels are high, but fail when levels are low (Jia et al., 2012, p. 652). This may indicate that asthma has many contributing factors other than IL-13 activation and treatments must be specified for each asthmatic group (Woodruff et al., 2009, p. 394). Woodruff et al. (2009) indicated that TH2 and IL-13 levels positively correlated with perisotin (Woodruff et al., 2009, pp. 389-390). This is significant because it is important to know which biomarker is being expressed, because this allows for a specified treatment plan, for example the drug Lebrikizumab, which is an IL-13 inhibitor, was effective in patients with high levels of periostin, but was not effective in patients with lower levels (Jia et al., 2012, p. 652).
Asthma is an inflammatory response caused by TH2 released ILs, specifically IL-13, which increases mucous production and promotes bronchial airway changes leading to an obstruction. IL-13 plays a vital role in initiating Alveolar macrophage recruitment, but doesn’t have a hand in prolonging the macrophage response. Alveolar macrophages may be induced to continue and prolong their functions by other mediators or they may be intrinsically activating themselves after an initial activation via IL-13. Damage to the airway is eventually caused by ROS and actions of alvelolar macrophages, and possibly by other immune cells. Remodelling must take place and is aided by IL-13 which activates fibroblasts. Levels of TH2 and IL-13 are not the same in all asthmatic patients, therefore treatments are only effective in patients who have high levels of these cells, but fail in those whose levels are low. Treatments need to be patient specific and can be given by testing patients for periostin levels in their lungs. Future studies can use new drug approaches to prevent IL-13 release, but targeting IL-13 may not always prevent asthmatic symptoms in all patients because mediators IL-4 and 5 are still active, therefore inhibiting TH2s might make sense, but this may lead to immunosuppression and may cause increased morbidity and mortality. More studies should look at specific biomarkers in different asthmatic patients. IL-13 is just a small portion in the large spectrum of mediators that cause asthma, and it is important to note that newer studies have linked IL-13 to contributing more to the asthma response.
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