Interleukin‐33 improves local immunity during Gram‐negative pneumonia by a combined effect on neutrophils and inflammatory monocytes

Abstract

Pneumonia represents a major health care burden and Gram‐negative bacteria provide an increasing therapeutic challenge at least in part through the emergence of multidrug‐resistant strains. IL‐33 is a multifunctional cytokine belonging to the IL‐1 family that can affect many different cell types. We sought here to determine the effect of recombinant IL‐33 on the host response during murine pneumonia caused by the common Gram‐negative pathogen Klebsiella pneumoniae. IL‐33 pretreatment prolonged survival for more than 1 day during lethal airway infection and decreased bacterial loads at the primary site of infection and distant organs. Postponed treatment with IL‐33 (3 h) also reduced bacterial growth and dissemination. IL‐33‐mediated protection was not observed in mice deficient for the IL‐33 receptor component IL‐1 receptor‐like 1. IL‐33 induced a brisk type 2 response, characterized by recruitment of type 2 innate lymphoid cells to the lungs and enhanced release of IL‐5 and IL‐13. However, neither absence of innate lymphoid cells or IL‐13, nor blocking of IL‐5 impacted on IL‐33 effects in mice infected with Klebsiella. Likewise, IL‐33 remained effective in reducing bacterial loads in mice lacking B, T, and natural killer T cells. Experiments using antibody‐mediated cell depletion indicated that neutrophils and inflammatory monocytes were of importance for antibacterial defense. The capacity of IL‐33 to restrict bacterial growth in the lungs was strongly reduced in mice depleted of both neutrophils and inflammatory monocytes, but not in mice selectively depleted of either one of these cell types. These results suggest that IL‐33 boosts host defense during bacterial pneumonia by a combined effect on neutrophils and inflammatory monocytes. © 2020 The Authors. The Journal of Pathology published by John Wiley & Sons, Ltd. on behalf of The Pathological Society of Great Britain and Ireland.

Mechanism of chlorogenic acid in alveolar macrophage polarization in Klebsiella pneumoniae-induced pneumonia

“…Kp promotes inflammatory infiltration and cytokine storm, manifested by overproduction of IL‐1β, IL‐6, TNF‐α, IL‐13, IL‐33, and IFN‐γ 35–37 . Initially, we established the pneumonia mouse model via Kp infection.…”

“…9,34 Moreover, SIRT1 acts as a crucial regulator of lung inflammation and macrophage polarization and modulates HMGB1 expression and acetylation. [35][36][37] HMGB1 inhibition plays a protecting role in Kp-infected mice and HMGB1 overexpression promotes proinflammatory polarization. 24,38 In the present study, we demonstrated that CA activates SIRT1 to inhibit HMGB1 acetylation and nuclear-cytoplasm translocation, thereby promoting M2 polarization and alleviating Kp-induced pneumonia (Figure 9).…”

Post-treatment with the PPAR-γ agonist pioglitazone inhibits inflammation and bacterial growth during Klebsiella pneumonia

“…Pneumonia was induced in female C57BL/6 mice (Charles River, Maastricht, the Netherlands; 8–10 weeks of age) by intranasal inoculation of K. pneumoniae serotype 2 (43816; ATCC, Rockville, MD; 10 4 colony‐forming units, CFU) as previously described [ 11 – 13 ]. Bacterial counts were determined in organ homogenates and blood as described [ 11 – 13 ].…”

“…Pneumonia was induced in female C57BL/6 mice (Charles River, Maastricht, the Netherlands; 8–10 weeks of age) by intranasal inoculation of K. pneumoniae serotype 2 (43816; ATCC, Rockville, MD; 10 4 colony‐forming units, CFU) as previously described [ 11 – 13 ]. Bacterial counts were determined in organ homogenates and blood as described [ 11 – 13 ]. Tumor necrosis factor (TNF)-α, interleukin (IL)-6, IL-1β, IL-10, C-X-C motif ligand (CXCL)2 and myeloperoxidase (MPO) were measured in lung homogenates by ELISA according to manufacturer’s instructions (R&D Systems, Minneapolis, MN, USA).…”

IL-33/ST2 Axis Plays a Protective Effect in Streptococcus pyogenes Infection through Strengthening of the Innate Immunity

“…ST2 deficiency improves the outcome of Staphylococcus aureus -induced septic arthritis using the intraarticular infection model [ 34 ]; in a systemic infection model induced by a lethal intravenous dose of S. aureus , IL-33 administration protects against lethality via ILC2-dependent type 2 cytokine production [ 35 ]; in post-influenza S. aureus pneumonia, IL-33 diminishes bacterial loads and mortality by an effect that does not require ILC2 cells [ 36 ]. Furthermore, IL-33 increases bacterial loads and lethality through induction of type 2 cytokines in Legionella pneumophila -induced pneumonia [ 37 ], while IL-33 improves local immunity during Klebsiella pneumoniae -induced pneumonia by a combined effect on neutrophils and inflammatory monocytes but not on B, T, NK and ILC2 cells [ 38 ].…”