Chronic obstructive pulmonary disease (COPD) presents a significant global health challenge characterized by progressive airflow limitation and persistent lung inflammation, stemming from both distal airways and parenchymal remodeling, due to failed regenerative processes [1], [2]. While cigarette smoke (CS) is widely recognized as a leading cause of COPD, certain cases of COPD in some regions worldwide may not be attributable to smoking. These non-smoking-related COPD cases encompass genetic factors, impaired lung development, exposure to biomass and pollution, respiratory infections, among others [3]. Despite our understanding of these contributors, the regulatory mechanisms governing lymphocytes, particularly macrophages and monocytes [4], [5], [6], involved in the inflammatory response associated with COPD remain elusive. This complexity poses challenges in the development of effective anti-inflammatory treatments for COPD.

The progression of COPD relies on the activation of specific inflammatory signaling pathways within cells, with the NF-κB inflammatory signal serving as a pivotal mediator for the secretion of inflammatory factors [7]. This orchestrated cascade, involving key inflammatory cytokines such as IL-1β, IL-6, and TNF-α, plays a central role in COPD pathogenesis [8]. Toll-like receptors (TLRs), commonly subject to dysregulation in COPD, modulate downstream MyD88, thereby activating the NF-κB inflammatory signaling pathway and contributing to COPD progression [9], [10]. Although our previous research, alongside others, has highlighted the upregulation of TLR2 in COPD lung monocytes [9], [11], [12], the regulatory dynamics of TLR2 expression in COPD monocytes remain largely unknown.

The exportin family, known for its involvement in the nucleocytoplasmic transport of proteins and RNAs, plays a vital role in cellular signal transduction. This family comprises seven members, including XPO1 (CRM1), XPO2 (CSE1L), XPO3 (XPOt), XPO4, XPO5, XPO6, and XPO7 [13], [14]. While XPO1 [15], XPO2 [16], XPO6 [17], and XPO7 [18] primarily mediate protein export, XPO3 [19], XPO4 [20] and XPO5 [21] are involved in the export of tRNAs, circRNAs and precursor microRNAs, respectively. Dysregulation of exportins has been linked to various diseases, including cancer and immune disorders [13], [22], [23], [24]. Despite their significance as upstream signals mediating pathophysiological functions, the role of exportins in COPD progression remains unexplored.

Herein, we investigated the potential involvement of the exportin family in COPD progression. Intriguingly, we consistently observed upregulation of XPO6 in pulmonary monocytes from both human and mouse COPD subjects. Our findings revealed a previously unexplored role of XPO6 in activating the TLR2/MyD88/NF-κB inflammation signaling pathway by facilitating TLR2 mRNA nuclear export in COPD pulmonary monocytes.