Effect of IL-10 on Neutrophil Recruitment and Survival afterPseudomonas aeruginosaChallenge

Abstract

IL-10 is a potent, endogenous anti-inflammatory cytokine known to decrease cytokine and keratinocyte-derived chemokine (KC) expression. Traditionally, in vivo effects of IL-10 were extrapolated from studies employing systemic antibody neutralization. As a result, divergent data regarding the protective and/or harmful roles of IL-10 have been reported. In this study, we used a lung-specific, tetracycline-inducible IL-10 overexpression-transgenic (IL-10 OE) mouse to study the effects of IL-10 overexpression on Pseudomonas aeruginosa-induced lung inflammation and corresponding survival in mice. Overexpression of IL-10 in the lung significantly increased mortality. During the early phase after infection (6-hours after infection), neutrophil recruitment as well as cytokine (TNF-alpha) and chemokine (KC) expression were significantly decreased in the IL-10 OE mice, which resulted in attenuated bacterial clearance. In contrast, overzealous production of KC and TNF-alpha intensified neutrophil infiltration and increased vascular leakage in IL-10 OE mice at the later stage of infection (24 hours after infection). Neutrophil depletion showed impaired bacterial clearance in both control and IL-10 OE mice, and further enhanced mouse mortality, whereas exogenous administration of KC reversed this finding. Our data indicate that early neutrophil recruitment is important for combating bacterial infection, and that the inhibition of neutrophil recruitment by IL-10 results in insufficient bacteria clearance in the lung, leading to excessive development of inflammation and increased mortality.

Coinfection with an Intestinal Helminth Impairs Host Innate Immunity against Salmonella enterica Serovar Typhimurium and Exacerbates Intestinal Inflammation in Mice

“…In line with our observations, an early study using the RAW 264.7 macrophage cell line showed that IL-10 inhibited production of MIP-1 and MIP-2 after lipopolysaccharide stimulation (31). The impact of IL-10 on neutrophil recruitment was also studied by using a lung-specific, tetracycline-inducible IL-10-overexpressing transgenic mouse (32). It was found that during the early phase of Pseudomonas aeruginosa infection, neutrophil recruitment and cytokine (TNF-␣) and chemokine (KC) expres- sion were significantly decreased in the IL-10 transgenic mice, which resulted in impaired clearance of P. aeruginosa (32).…”

“…The impact of IL-10 on neutrophil recruitment was also studied by using a lung-specific, tetracycline-inducible IL-10-overexpressing transgenic mouse (32). It was found that during the early phase of Pseudomonas aeruginosa infection, neutrophil recruitment and cytokine (TNF-␣) and chemokine (KC) expres- sion were significantly decreased in the IL-10 transgenic mice, which resulted in impaired clearance of P. aeruginosa (32). It has been shown previously that IL-10 reduces the stability of a number of mRNAs, including KC, TNF-␣, and MIP-1 (33,34).…”

Lung Natural Killer Cells Play a Major Counter-Regulatory Role in Pulmonary Vascular Hyperpermeability After Myocardial Infarction

“…However, the impact of systemic IL-10 is determined by the timing of application and the underlying disease, whereby in states of sterile inflammation it may be beneficial but deleterious in infection. 30 In this study, we demonstrated that post-MI pulmonary edema engaged NK cells in an IL-10-mediated immunoregulatory circuit that functions to alleviate pulmonary edema.…”

Activated β2 Integrins Restrict Neutrophil Recruitment during Murine Acute Pseudomonal Pneumonia

“…Neutrophils are essential for host defense against P. aeruginosa and other bacterial infections of the lungs (32,(36)(37)(38). Neutropenic human patients (39,40) and laboratory mice (36,41,42) have enhanced susceptibility to pseudomonal pneumonia.…”