**1. Introduction**

Asthma is a chronic respiratory disease that is usually associated with inflammation and remodeling of the airways. Subepithelial fibrosis is a characteristic hallmark of airway remodeling in asthma, particularly in patients with severe asthma [1]. Unfortunately, current asthma medications cannot sufficiently target and ameliorate subepithelial fibrosis. Therefore, a deeper understanding of the fibrotic mechanisms in action is essential to identify novel therapeutic targets. This could aid in ameliorating fibrosis and improving the airway dynamics in asthma patients.

**Citation:** Ramakrishnan, R.K.; Bajbouj, K.; Guimei, M.; Rawat, S.S.; Kalaji, Z.; Hachim, M.Y.; Mahboub, B.; Ibrahim, S.M.; Hamoudi, R.; Halwani, R.; et al. Bcl10 Regulates Lipopolysaccharide-Induced Pro-Fibrotic Signaling in Bronchial Fibroblasts from Severe Asthma Patients. *Biomedicines* **2022**, *10*, 1716. https://doi.org/10.3390/ biomedicines10071716

Academic Editor: Stanislawa Bazan-Socha

Received: 31 May 2022 Accepted: 30 June 2022 Published: 15 July 2022

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**Copyright:** © 2022 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https:// creativecommons.org/licenses/by/ 4.0/).

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The Nuclear factor (NF)-kappaB (NF-κB) signaling pathway is a highly versatile pathway that plays a vital role in multiple biological processes, including cell growth, survival, development, immune response and inflammation [2]. NF-κB is a key signaling pathway in asthma pathogenesis, particularly in airway inflammation. Persistent activation of the NFκB pathway was noted in peripheral blood mononuclear cells isolated from patients with severe uncontrolled asthma [3]. As a result, increased levels of pro-inflammatory mediators were secreted by these cells despite continuous systemic glucocorticoid treatment. At the same time, activation of NF-κB signaling has also been noted in lung fibroblasts during fibrogenesis [4]. Furthermore, NF-κB activation induces the expression of pro-fibrotic cytokines such as IL-6, IL-8 and TGF-β [5–7].

B-cell lymphoma/leukemia 10 (Bcl10) is an adaptor protein associated with the constitutive activation of canonical NF-κB in mucosa-associated lymphoid tissue (MALT) B cell lymphoma [8]. Bcl10 has been largely studied in antigen receptor-mediated lymphocyte activation, where it was found to interact with CARMA/CARD-containing scaffold proteins and MALT1 paracaspase to form the three-component CBM signalosome that sets in motion a cascade of events that eventually lead to NF-κB induction [9,10]. Depending on the cell-specific chromatin landscape accessible to NF-κB or other transcription factors, the activation of this pathway through CBM complex signaling results in the inducible expression of numerous inflammatory cytokines, chemokines and factors that control cellular functions, including survival, proliferation and differentiation [11]. Thus, CBM signaling is essential for host defense and tissue homeostasis. However, alterations in the signaling components, including Bcl10, have been implicated in diseases such as autoinflammatory diseases, lymphoproliferative disorders and immunodeficiencies, as well as cancers [12].

Bcl10 signaling plays an important role in establishing the inflammatory environment associated with asthma. Bcl10 is involved in FcεRI-mediated NF-κB activation, pro-inflammatory cytokine release and degranulation of mast cells [13]. IgE-mediated allergic inflammatory response was found to be impaired in Bcl10-deficient mast cells [13,14], indicating Bcl10 as a key regulator of immune signaling in mast cells. Furthermore, Bcl10 also complexes with CARMA3/CARD10 and MALT1 to form the CBM-3 signalosome as a result of G-protein-coupled receptor (GPCR) activation to induce pro-inflammatory gene expression in non-immune cells such as fibroblasts and endothelial cells [15].

Interestingly, studies also indicate Bcl10 to be an important mediator of fibrotic remodeling. Angiotensin II (Ang II)-induced fibrotic signaling, such as extracellular matrix (ECM) synthesis and myofibroblast proliferation, was mediated by Bcl10 via the CBM-3 signalosome [16,17]. Bcl10 also regulated lipopolysaccharide (LPS)-induced activation of NF-κB and IL-8 in human intestinal epithelial cells [18], suggesting a role for Bcl10 in epithelial inflammation. Moreover, NF-κB-regulated genes in the airway epithelium contributed to allergen-induced peribronchial fibrosis and mucus production [19].

NF-κB activation is increasingly recognized in the pathogenesis of asthma and Bcl10 mediated NF-κB signaling has widely been studied as an inflammatory pathway in immune cells [20]. However, the role of Bcl10-driven NF-κB activation is yet to be explored in the context of airway remodeling in asthma. Since Bcl10 is an important mediator of fibrotic remodeling in other disease models, we hypothesized that the Bcl10-mediated NF-κB pathway promotes fibrotic signaling in severe asthmatic fibroblasts.
