Boosting the IL-22 response using flagellin prevents bacterial infection in cigarette smoke-exposed mice

Abstract

Summary The progression of chronic obstructive pulmonary disease (COPD), a lung inflammatory disease being the fourth cause of death worldwide, is marked by acute exacerbations. These episodes are mainly caused by bacterial infections, frequently due to Streptococcus pneumoniae. This susceptibility to infection involves a defect in interleukin (IL)-22, which plays a pivotal role in mucosal defense mechanism. Administration of flagellin, a Toll-like receptor 5 (TLR-5) agonist, can protect mice and primates against respiratory infections in a non-pathological background. We hypothesized that TLR-5-mediated stimulation of innate immunity might improve the development of bacteria-induced exacerbations in a COPD context. Mice chronically exposed to cigarette smoke (CS), mimicking COPD symptoms, are infected with S. pneumoniae, and treated in a preventive and a delayed manner with flagellin. Both treatments induced a lower bacterial load in the lungs and blood, and strongly reduced the inflammation and lung lesions associated with the infection. This protection implicated an enhanced production of IL-22 and involved the recirculation of soluble factors secreted by spleen cells. This is also associated with higher levels of the S100A8 anti-microbial peptide in the lung. Furthermore, human mononuclear cells from non-smokers were able to respond to recombinant flagellin by increasing IL-22 production while active smoker cells do not, a defect associated with an altered IL-23 production. This study shows that stimulation of innate immunity by a TLR-5 ligand reduces CS-induced susceptibility to bacterial infection in mice, and should be considered in therapeutic strategies against COPD exacerbations.

The Toll-Like Receptor 5 agonist flagellin prevents Non-typeable Haemophilus influenzae-induced infection in cigarette smoke-exposed mice

“…Through this mechanism, FliC might prime the antibacterial activity of effector cells including macrophages and neutrophils. We can also suspect that this treatment restores the barrier function of the airway mucosa since bacteria translocation within the blood is also decreased in CS-exposed mice (S1 Fig) . Whereas our data show that the treatment with FliC promotes the production of calgranulins in Sp-infected mice [26], this is not the case after NTHi infection. It has been reported that S100A8 and 9 are induced by both SP-and NTHi-infection, and they are major players in the host response against pneumococcal infection by increasing lung recruitment of neutrophils and macrophages [34,35].…”

“…Since the pathophysiology of COPD exacerbation episodes implicated a defect in IL-22 production and a deleterious effect of neutrophils on lung function, we choose to treat our mice by intraperitoneal route rather than a local administration which promotes a strong neutrophil recruitment in the airways. As previously reported with Sp in control (non COPD) mice [20,31,32] and in CS-exposed mice [26], the systemic treatment with FliC in NTHi-infected mice increases the IL-22 production in the BAL and in the supernatant of restimulated pulmonary cells without increase of the number and the activation of DC and AM in the airways. Nevertheless, we cannot exclude that the increased ability to produce IL-22 was linked to the recruitment of some populations of lymphocytes including T cells and NKT cells in CS-exposd mice.…”

“…Interestingly, the clearance of the bacteria was associated with a reduced inflammatory infiltrate and a decreased production of inflammatory cytokines in the lung of CS-exposed mice resulting in a less intense remodeling of lung tissues. Moreover, this treatment is also able to promote the NTHi-induced IL-22 production by PBMNC from healthy subjects [ 26 ].…”

IL-20 Cytokines Are Involved in Epithelial Lesions Associated with Virus-Induced COPD Exacerbation in Mice

“…Data were acquired on a LSR Fortessa (BD Biosciences, Franklin Lakes, United States) and analyzed with FlowJo™ software v7.6.5 (Stanford, CA, USA). Gating strategy has been previously described [ 8 , 19 ]. Absolute cell numbers were calculated according to the total cell number and the frequency of CD45+ immune cells.…”

“…Moreover, IL-17 and IL-22 are essential in order to prevent secondary bacterial invasion. Indeed, these cytokines orchestrate the anti-bacterial response against different bacteria by modulating the secretion of antimicrobial peptides [ 8 ]. IL-22 with IL-19, IL-20, IL-24 and IL-26 belong to the IL-20 cytokine subfamily.…”