The C1q Receptor Calreticulin Contributes to the Pathogenesis of Asthma
The C1q receptor functions as a stress response protein, a cellular calcium regulator, and as a cell death mediator. Thereby it contributes to carcinogenesis and controls innate immunity and. First described as an intracellular protein, the C1q receptor also integrates into the cell membrane and mediates the response to extracellular stimuli including collagen degradation fragments, bacterial wall proteins and complement proteins. However, its role in chronic inflammatory diseases has not been investigated in details. Recent evidence suggests that in chronic inflammatory lung diseases the C1q receptor contributes to infection induced exacerbation, which is the major cause of increased morbidity and mortality. In isolated human airway smooth muscle cells, the C1q receptorregulates translation control and thus, can function on the level of epigenetic protein control. In this function, the C1q receptor deregulation may lead to hyperplasia of airway smooth muscle cells, which is well documented in asthma. Furthermore, there are studies indicating that the C1q receptor is a positive regulator for a number of asthma relevant pro inflammatory cytokines, growth factors, and extracellular matrix compounds. In regard to asthma exacerbation, it is interesting to know that several bacteria and viruses encode for their own specific C1q receptor or the C1q receptor like protein, which interacts with its binding proteins on the host cells just as a host own C1q receptor. Thereby, the micro organisms C1q receptor can hijack the host cellular regulation system. This review presents supportive data for the hypothesis that deregulation of the C1q receptor is a major event leading to multiple asthma specific pathologies of the airway. Michael Roth* Department of Pulmonary Cell Research and Clinics of Pneumology, University Hospital Basel, Switzerland Michael Roth Journal of Respiratory Medicine and Lung Disease Remedy Publications LLC. 2016 Volume 1 Issue 1 Article 1002 2 sudden changes of air humidity often occurring in water and winter sport activities, severe anger or fear, and other physical exercise, obesity, or specific medication such as aspirin, non steroid antiinflammatory drugs, or b2 agonists [15 21] The main stand of asthma therapy consists of combined anti inflammatory and muscle relaxing drugs, mainly inhaled corticosteroids (ICS) combined with long acting b2 agonsist (LABA) [22,23] The major therapeutic effect of ICS results from their antiinflammatory action which is achieved by the activation of the intracellular glucocorticoid receptor and by the modification of DNA accessibility through his tone modification [22] There is controversial data if LABA have any anti inflammatory effect or if their action is restricted to the relaxation of muscle cells [23] Studying the effect of these drugs in isolated human airway cells, we were the first to provide the molecular biological mechanism that underlies the beneficial interaction of ICS and LABA [24 26] This mechanism was later confirmed in tissues of asthma and COPD patients by others [27,28] However, none of the drug has shown reduction of existing airway wall remodelling and there is data indicating that ICS, if taken in non acute stages may even worsen remodelling, since under noninflamed condition, these drugs increase the deposition of different extracellular matrix components [29,30] This hypothesis was supported by a study in patients with mild asthma, in which airway wall remodelling occurred within 4 days after allergen or cholinergic stimulus inhalation [31] In this study airway wall remodelling was only reduced in those patients who received inhaled b2 agonists before the inhalation of the stimulus. In this regard it is of interest that increased levels of extracellular matrix degradation products have been reported in isolated human airway wall cells as well as in tissue and serum samples obtained from asthma patients, but their link to the pathogenesis is still not well understood [32 36] Since the C1q receptor has been reported to modify extracellular matrix composition and respond to its degradation products, its contribution to the pathogenesis of asthma is suggested [37] The C1q receptor as a regulator of innate immunity The C1q receptor, which is also known as calreticulin, surfactant protein receptor, mannan binding ligand receptor, C1qR, CD93 or Aa4, is a ubiquitous, highly conserved calcium binding protein which is mainly located in the sarcoplasmic and endoplasmic reticulum. In addition, it has been localized as a cell membrane protein. As predicted by its structure the C1q receptor binds to hormone receptors, heat shock proteins (Hsp) integrins, viral and bacterial proteins, extracellular matrix components such as collagens, cell debris and cytokines [38] In the nucleus membrane the C1q receptor controls the in and out of the activated glucocorticoid receptor in other than lung cell types and might therefore be responsible for steroid resistance [39,40] These studies also showed that the function of the C1q receptor as a proor anti inflammatory factor depends on its partnering proteins, the cell type, and on its localisation within a cell. Most often asthma exacerbations are due to viral or bacterial infection [41] Thus it is important to note that complexes formed by pathogenic organism proteins and the C1q receptor stimulated phagocytosis, pro inflammatory response, but also extended the survival of the host cells [42] Interestingly, the membranous C1qreceptor directly interacts with various proteins that participate in innate immunity and asthma associated exacerbation including collectins such as ficolin [43] and manose binding lectins [44,45] Furthermore, the interaction of collectins with the C1q receptor depends on glycosilation [46] which we have reported to be altered in asthma and chronic obstructive pulmonary disease (COPD) [47,48] Both ficolin and MBLs have been related to increased exacerbation frequencies in asthma [49,50] and frequent infection as well as to oxidative stress in COPD [51] Collectins and complement components bind and activate the C1q receptor and have already been linked to the regulation of innate immune response in the late 1990's [52,53].In the lung, collectins have also been shown to modify innate immunity through activation of the C1q receptor [54] In a rat model, it was shown that the C1qreceptor is the central regulator of natural killer cell activity [55] The activation of the C1q receptor also controls the differentiation of monocyte derived dendritic cells through modification of innate and acquired immunity [56] Platelet activation by the action of the C1q receptor has been linked to collagen derived peptides which may be relevant for the modification of innate immunity in response to tissue remodelling [57] A further function of the C1q receptor is its role as a marker for cells to undergo apoptosis which is resolved by macrophage phagocytosis [58] Further studies showed that complement activation of the C1q receptor should be regarded as a unique sensor for "danger signal" which trigger the innate immune response [59] The known activators of the C1q receptors are shown in (Figure 1) The C1q receptor in the regulation of pro inflammatory cytokines in asthma Activation of the C1q receptor increases IL 6 and IL 8 secretion, which are both important to general immune activation and infiltration of eosinophils into the asthmatic lung [60] Interestingly, this effect of C1q receptor seems to be highly conserved through evolution [61] This action involves TNF a, another asthma relevant cytokine, which subsequently induces the signalling cascade of mitogen activated protein kinases [62] and their target NFKB [63,64] Interestingly, soluble C1q receptor can also induce the production of TNF a and IL 6 by macrophages [63] which makes it likely that this pathway represents the activation of the host cells in response to bacterial or viral infections through the micro organisms own calreticulin [65 70] Interestingly, the reduction of the C1q receptor Figure 1: The membranous C1q receptor functions as the mediator of many extracellular factors, including: manose binding lectin (MBL) surfactant protein (SP) and complement component 1 (C1q) NK natural killer cell. Michael Roth Journal of Respiratory Medicine and Lung Disease Remedy Publications LLC. 2016 Volume 1 Issue 1 Article 1002 3 expression stabilized the inhibitor of NFKB, IKB, thereby reducing histone modification and cytokine secretion [64] In cardio myocytes of mice, it has been observed that glutathione depletion increased the C1q receptor expression and thereby enhanced myocyte proliferation [71] The C1q receptor controls protein folding when it is located in the endoplasmic reticulum where it has been shown to modify the structure of IL 12a and b [72] A similar effect of the C1q receptor was reported on IL 23 [73] Furthermore, C1q receptor affects the expansion of B cells and the secretion of IL 10 [74] In T cells, the C1q receptor enhanced IFN g secretion and the expression of CD40 on dendritic cells [75] Finally in macrophages, the C1q receptor induced autophagy through the activation of IL 1b [76] A summary of the effects of the C1q receptor on cytokine release is shown in (Figure 2) The role of the C1q receptor in airway wall remodelling Beside chronic inflammation, asthma is characterised by extensive airway wall remodelling, presenting as increased mass of smooth muscle bundles, sub epithelial fibrosis, and extracellular matrix deposition, which were first described in 1922 [77] This major pathology was believed to increase with the duration of the disease but it has recently been demonstrated that it can be induced within days and is independent of inflammation and was related to constrictive forces in the airway wall [31] Once established, the remodelled airway wall is largely resistant