Adaptive immune responses and protein homeostasis in COPD: the immunoproteasome

Whether exaggerated immune responses cause inflammation-derived damage in COPD or whether the cigarette smoke-induced inflammatory cascade is the ultimate cause of the immune system activation in COPD is a never-ending chicken-and-egg debate. In any case, the era when COPD pathogenesis seemed to revolve solely around CD8⁺ T cells and macrophages seems long gone. As the resources to dissect cellular biology advance, we have shifted our magnifying glass from the main cell types characterising a specific disease, to their subcellular functions. In particular, recent studies pointed at mechanisms involving altered protein homeostasis (proteostasis), such as unfolded protein responses and endoplasmic reticulum stress, and inhibition of the ubiquitin-proteasome system, as key in COPD pathogenesis [1, 2]. This dysfunctional protein processing ultimately leads to the accumulation of nonfunctional and potentially cytotoxic, misfolded proteins that contribute to lung cell apoptosis, inflammation and autophagy typical of COPD.

The ubiquitin-proteasome system is involved in the control of nearly all biological processes in cells. The ubiquitin-proteasome system has a prominent role in the immune system, but the mechanisms linking immune homeostasis and protein regulation are unknown. The exciting study from Kammerl et al. [3] has the unique merit of merging two critical aspects of COPD pathogenesis: immune cell dysfunction and aberrant protein degradation, by investigating the “immunoproteasome”, a specialised type of proteasome present in the immune cells. The immune cells, particularly T cells, use the immunoproteasome for efficient antigen processing and their homeostasis and differentiation [4]. Notably, the immunoproteasome activity promotes differentiation of pro-inflammatory T helper type 1 (Th1) and type 17 (Th17) cells while suppressing induction of regulatory T cells [5], which are both key features of advanced COPD (figure 1). In fact, the rapid assembly rate of the immunoproteasome subunits is approximately four times faster than assembly of the constitutive proteasomes, enabling a rapid response to immune and inflammatory stimuli [6], such as cigarette smoke.

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FIGURE 1

Proposed role of the immunoproteasome in COPD: COPD-related antigens, such as cigarette smoke, viral and/or bacterial, and possibly other antigens of unknown origin contribute to immune cell recruitment and activation. On one hand, circulating immune cells are attracted into the lung by chemokines and lymphokines, causing lung tissue damage and destruction. On the other hand, the circulating immunoproteasome is activated in response to these antigens, and induces changes in adaptive immune populations such as increased T cell differentiation via molecular histocompatibility complex I (MHC-I)–T cell receptor (TCR) interaction, upregulation of T helper type 17 (Th17) cells, (autoreactive) B cells, and down-regulation of regulatory T cells, contributing to the inflammation, lung tissue damage and autoimmune phenomena observed in COPD. As a result of these processes, extracellular matrix degradation and release of elastin peptides and unfolded protein responses occur in the COPD lung. These released proteins further activate the immunoproteasome, creating a vicious circle leading to exacerbated lung inflammation, tissue destruction, and COPD progression.

In their study, Kammerl et al. [3] assess the expression and the activation status of the immunoproteasome in peripheral blood cells of patients with severe COPD versus young smokers without COPD. The immunoproteasome is composed of a 26S core proteasome consisting of the 20S central catalytic core and one or two 19S regulators. In turn, the 20S core includes three immune-subunits, LMP2, MECL-1 and LMP7, that are constitutively expressed at high levels in immune cells, but can also be induced by several stimuli, such as interferon (IFN)-γ. This characteristic, which is not present in the general (not immune) proteasome, enables the immunoproteasome to respond quickly and efficiently to inflammatory signals and stressors. Due to its fast and dynamic changes reflecting the inflammatory and immune status of a specific organ system, the immunoproteasome is gaining increasing attention in the field of COPD as it might represent a potential circulating biomarker for COPD severity, disease progression and, possibly, exacerbation frequency.

This work from Kammerl et al. [3] branches from previous studies from the same group that showed that, in the lung, immunoproteasome expression and activity are inhibited by cigarette smoke [7, 8], especially in patients with end-stage COPD, resulting in accumulation of oxidatively damaged proteins and altered major histocompatibility class I antigen presentation. In the present study the authors show that, in circulating immune cells from COPD patients, the protein levels of 26S immunoproteasome and its subunits were elevated, and the 26S proteasome activity was increased. At first, this might seem in contrast with previous data published by the same group. However, as the authors pointed out, the targeted responses involving circulating immune cells are transient due to the shorter life of the latter compared to immune cells harboured in the lung, and the observed activation of the 26S immunoproteasome complex in circulating cells might reflect a temporary and yet blunted response to a noxa (for example, cigarette smoke or virus infection; figure 1). As a result, peripheral immune cells of COPD patients undergo transcriptional activation upon cigarette smoke-induced inflammation, and the increased assembly and activity of the immunoproteasome might be a consequence of such epigenetic changes.

Furthermore, the authors found a significant strong inverse correlation between the activation of 20S (one of the 26S subunits) and lung function in COPD, and a direct correlation between 26S activity and lung function in COPD. Importantly, these changes in the immunoproteasome function appeared to be closely specific to severe COPD, as they persisted even after correction for multiple parameters such as age, sex, body mass index, comorbidities and immune medications, and after sensitivity analyses aimed at evaluating the role of the smoking status on the primary outcomes. This finding, while it adds an additional layer of complexity to the known functions of the immunoproteasome, paves the way to novel approaches to the study of proteins and proteasomes in COPD. In fact, this is the first evidence that specific subunits of the immunoproteasome function are differentially activated in severe COPD and independently from cigarette smoke. Apart from the clear therapeutic implications that this finding might have, this new piece of information may create a bridge between the role of (in particular adaptive) immune cells and the protein turnover and degradation contributing to onset and progression of COPD. If, on one hand, it is well established that blunted adaptive immune responses involving T and B cells are crucial in the pathogenesis of COPD [9, 10], with B cells playing a major role in the self-perpetuation of inflammatory loops in the lung and blood from patients with severe COPD [11, 12], on the other it is unclear whether the destruction of lung parenchyma observed in severe stage of COPD is a direct effect or an epi-phenomenon of these off-targeted immune responses. Kammerl et al. [3] now show that immune cells directly contribute the protein homeostasis in COPD, suggesting that the increased circulating immunoproteasome activity might be not only part of an adaptive response to the increased oxidatively modified and damaged protein turnover known to be elevated in severe COPD, but also a way the adaptive immune system establishes a self-perpetuating activation loop in response to yet unknown COPD-related antigens (figure 1). In COPD, these upregulated adaptive immune responses end up being detrimental and self-reactive, and further exacerbate the lung damage. Interestingly, the immunoproteasome inhibition ameliorates disease symptoms in different animal models of autoimmune diseases [13]. Two major pathways involved in disease development are affected by immunoproteasome inhibition, namely, cytokine secretion and T helper cell differentiation. Inhibition (or deficiency) of the immunoproteasome strongly reduces T cell receptor-dependent activation of T cells and endotoxin-stimulated human circulating immune cells [14], suppressing pro-inflammatory cytokine secretion, plasma cell-mediated antibody production and Th17 differentiation (figure 1) [15–17], confirming an extended function for immunoproteasomes in the autoimmune phenomena underlying COPD progression directly involving immune cells as active source of inflammation and not as bystanders.

This brings us to the last and most important implication of this new finding: how do we tackle this newly discovered role of the immunoproteasome in the onset and/or progression of COPD? The authors speculate that immunoproteasome inhibitors may contribute to the restoration of the dysfunctional immune system in COPD, without hinting at the possible mechanism underlying. However, they do provide evidence that the COPD immunoproteasome is further activated upon ex vivo stimulation of circulating immune cells with the inflammatory cytokine IFN-γ or lipopolysaccharide (LPS), both crucial in COPD pathogenesis. Also, specific inhibition of the immunoproteasome attenuates LPS-induced expression of pro-inflammatory cytokines and increases the expression of anti-inflammatory cytokines such as IL-10. Obviously, this potential therapeutic approach to COPD is appealing; however, several aspects need to be clarified. First, whether the inhibition of the immunoproteasome as a whole or only some subunits need to occur in order to shut down the detrimental, and boost the protective, activities of the proteasome; second, whether identifying and targeting the main immune cellular source of the proteasome could be a viable strategy to dampen the immunoproteasome-related damages; and third, what is the target population that might benefit from strategies aimed at inhibiting the proteasome expression and/or activity, whether it would be only end-stage COPD patients, as the study from Kammerl et al. [3] suggests, stable COPD or COPD exacerbators, given the strong response of the immunoproteasome to LPS stimulation.

To conclude, the study from Kammerl et al. [3] provides an interesting, novel insight into immune cell functions that go beyond the orchestration of inflammatory responses to cigarette smoke and other antigens in COPD. Exactly what the immunoproteasome is doing in COPD onset and progression remains unclear. Implying causality would exceed the associational, cross-sectional nature of the data, and was wisely not claimed. Future studies, possibly with pre-clinical models of COPD, will need to test the exact role of the immunoproteasome in COPD, and the therapeutic advantages that could arise from its manipulation. There is an opportunity to move the immunoproteasome to the centre stage of COPD pathology.

• Received September 23, 2021.
• Accepted September 24, 2021.

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