A systemic defect in Toll-like receptor 4 signaling increases lipopolysaccharide-induced suppression of IL-2-dependent T-cell proliferation in COPD

Abstract

The susceptibility to bacterial infections is increased in chronic obstructive pulmonary disease (COPD). This promotes exacerbations. IL-2 triggers CD4(+)/Th1-cell proliferation, which is important for infection defense. Bacterial endotoxin (LPS) activates MyD88/IRAK and TRIF/IKKε/TBK1 pathways via Toll-like receptor-4 (TLR4) in Th1 cells. Systemic defects in TLR pathways in CD4(+)/Th1 cells cause an impairment of IL-2-dependent immune responses to bacterial infections in COPD. Peripheral blood CD4(+) T cells of never smokers, smokers without COPD, and smokers with COPD (each n = 10) were ex vivo activated towards Th1 and stimulated with LPS. IL-2, MyD88, and TRIF expression, and cell proliferation was analyzed by ELISA, quantitative RT-PCR, and bromodeoxyuridine (BrdU) and trypan blue staining comparative among the cohorts. IL-2 release from activated T cells was increased in COPD vs. smokers and never smokers. LPS reduced IL-2 expression and T-cell proliferation. These effects were increased in COPD vs. never smokers and inversely correlated with FEV1 (%predicted). The MyD88/TRIF ratio was decreased in Th1 cells of COPD. The suppression of IL-2 by LPS was abolished by MyD88/IRAK blockade in never smokers but by TRIF/IKKε/TBK1 blockade in COPD. Moxifloxacin restored IL-2 expression and T-cell proliferation in the presence of LPS by blocking p38 MAPK. The increased IL-2 release from Th1 cells in COPD might contribute to airway inflammation in disease exacerbations. A switch from MyD88/IRAK to TRIF/IKKε/TBK1 signaling amplifies the suppression of IL-2-dependent proliferation of CD4(+) T cells by LPS in COPD. This molecular pathology is of systemic origin, might impair adaptive immune responses, and could explain the increased susceptibility to bacterial infections in COPD. Targeting TLR4-downstream signaling, for example, with moxifloxacin, might reduce exacerbation rates.

LPS enhances TLR4 expression and IFN-γ production via the TLR4/IRAK/NF-κB signaling pathway in rat pulmonary arterial smooth muscle cells

“…Passive smoking and intratracheal instillation of LPS may cause lung injury similar to chronic obstructive pulmonary disease via the NF-κB signaling pathway, and TLR4 serves an important role in this process (16). A systemic defect in TLR4 signaling increases lipopolysaccharide-induced suppression of IL-2-dependent T-cell proliferation in COPD (3). The TLR4/MyD88 pathway is activated and its downstream inflammatory cytokines such as TNF-α and IL-6 were increased in macrophages from COPD patients (17).…”

“…Toll-like receptors (TLRs) are receptors that have the prominent biological function to promote synthesis and release of cytokines to trigger inflammatory response (3). Moreover, it also can promote the maturation of antigen presenting cells to induce the human body's acquired immunity.…”

Pulmonary Epithelial TLR4 Activation Leads to Lung Injury in Neonatal Necrotizing Enterocolitis

“…Specifically, while TLR4 plays a critically important role in host defense and coordination of the adaptive and innate immune responses when expressed on leukocytes(47), exaggerated TLR4 signaling on mucosal surfaces can lead to tissue injury in the liver (48), pancreas (49, 50)and small intestine (8, 51, 52). TLR4 signaling in the lung can also induce pro-inflammatory signaling in chronic obstructive pulmonary disease (21) and asthma (22), and has been shown to induce inflammatory changes in response to the endogenous ligand hyaluronan in the setting of acute lung injury (23). Despite these important studies, it has not been possible to reliably determine whether the role for TLR4 signaling in these disease processes acts on the lung epithelium or on other cell types, due to the lack of available mice in which TLR4 is deleted from the pulmonary epithelium.…”

“…Thus, in the postnatal period, persistently elevated TLR4 expression on the still premature intestinal epithelium interacts with colonizing microbes and causes a pro-inflammatory response leading to mucosal injury (14, 15), while TLR4 signaling on the endothelium leads to impaired gut perfusion and mucosal death (20). TLR4 has also been shown to be expressed in the lung (21) (22, 23), where it may either contribute to or protect from the development of lung disease – a seeming contradiction that has not been fully resolved, in part due to the lack of mice deficient in TLR4 on the pulmonary epithelium.…”

B cells in chronic obstructive pulmonary disease: moving to center stage

“…Mechanisms exist that perpetuate and amplify pulmonary inflammation in COPD lungs as chronic pulmonary inflammation often increases progressively as COPD severity increases and can persist after smoking cessation. Early studies focused on the activities of innate immune cells (25,26,31,62) and then CD8ϩ and CD4ϩ T cells in the pathogenesis of COPD (32,38,68). More recently, B cells have been linked to COPD as there are increases in the number and size of B cell-rich lymphoid follicles (LFs) in the severe stages of COPD and the presence of B cell products (autoantibodies) in COPD blood and lung samples (42,54,59).…”