IL-22 Defect During Streptococcus pneumoniae Infection Triggers Exacerbation of Chronic Obstructive Pulmonary Disease

Abstract

Progression of chronic obstructive pulmonary disease (COPD) is linked to episodes of exacerbations caused by bacterial infections due to Streptococcus pneumoniae. Our objective was to identify during COPD, factors of susceptibility to bacterial infections among cytokine network and their role in COPD exacerbations. S. pneumoniae was used to sub-lethally challenge mice chronically exposed to air or cigarette smoke (CS) and to stimulate peripheral blood mononuclear cells (PBMC) from non-smokers, smokers and COPD patients. The immune response and the cytokine production were evaluated. Delayed clearance of the bacteria and stronger lung inflammation observed in infected CS-exposed mice were associated with an altered production of IL-17 and IL-22 by innate immune cells. This defect was related to a reduced production of IL-1β and IL-23 by antigen presenting cells. Importantly, supplementation with recombinant IL-22 restored bacterial clearance in CS-exposed mice and limited lung alteration. In contrast with non-smokers, blood NK and NKT cells from COPD patients failed to increase IL-17 and IL-22 levels in response to S. pneumoniae, in association with a defect in IL-1β and IL-23 secretion. This study identified IL-17 and IL-22 as susceptibility factors in COPD exacerbation. Therefore targeting such cytokines could represent a potent strategy to control COPD exacerbation.

Randomized Phase I Healthy Volunteer Study of UTTR1147A (IL‐22Fc): A Potential Therapy for Epithelial Injury

“…Gastrointestinal disorders 7 (50.0%) [12] 1 (50.0%) [ Hyperesthesia -------3 (75.0%) [6] 3 (11.5%) [6] Placebo SC (n = 10) Overall total 8 (80.0%) [25] 5 (100.0%) [21] 4 (100.0%) [22] 4 (100.0%) [25] 4 (100.0%) [ 4 (100.0%) [7] 4 (100.0%) [12] 4 (100.0%) [7] 1 (100.0%) [3] 18 (100.0%) [37] Injection-site discoloration One subject in the placebo group received a minimal amount of UTTR1147A instead of placebo due to a pharmacy error. This subject developed a small patch of mild erythema at the injection site, which completely resolved by study end.…”

“…For example, IL‐22 has shown therapeutic benefits in mouse models of colitis, hepatitis, acute kidney injury, pancreatitis, and skin wound healing . IL‐22 may also support regeneration in other tissues, such as the thymus, and may protect against systemic bacterial infections originating in the lungs or intestines …”

“…For example, IL-22 has shown therapeutic benefits in mouse models of colitis, hepatitis, acute kidney injury, pancreatitis, and skin wound healing. [7][8][9][10][11][12][13][14][15][16][17] IL-22 may also support regeneration in other tissues, such as the thymus, 18 and may protect against systemic bacterial infections originating in the lungs [19][20][21] or intestines. 22 UTTR1147A (IL-22Fc) is a fusion protein of human IL-22 linked to the crystallizable fragment (Fc) of human immunoglobulin (Ig)G4 to increase its stability in vivo.…”

Preclinical Efficacy of a Trivalent Human FcγRI-Targeted Adjuvant-Free Subunit Mucosal Vaccine against Pulmonary Pneumococcal Infection

“…Specifically, we evaluated the secretory antibody response, which plays an important role in restricting bacterial invasion through the mucosa. Apart from the secretory antibodies, cytokines produced by T helper-17 (Th17) and T helper-22 (Th22) cells have been shown to play important roles in protection against several S. pneumoniae strains [14][15][16][17]. Specifically, IL-17 and IL-22 produced by these cells together induce secretion of chemokines and antimicrobial peptides, as well as recruitment of neutrophils, which promote bacterial clearance [18].…”

Th17 profile in COPD exacerbations

“…30 On the other hand, IL-22 has been linked to multiple pathologies of an inflammatory nature, for example, psoriasis and rheumatoid arthritis, in addition to having an important role in the defense of the lungs against pathogens, especially extracellular bacteria, assisting production and release, for example, of defensins in the mucosa of the airways, in addition to maintaining the integrity of the epithelium. 31 A study by Pichavant et al 31 showed that, during Streptococcus pneumoniae infections in mice exposed to cigar smoke, cytokine levels related to Th17 lymphocytes are decreased, leading to exacerbations. 33 In addition, IL-23 is associated with maintenance of the response generated by this group of cooperating T lymphocytes.…”