No 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.

Background Complement factor C5 can either aggravate or attenuate the T-helper type 2 (T H 2) immune response and airway hyperresponsiveness (AHR) in murine models of allergic asthma. The effect of C5 during the effector phase of allergen-induced asthma is ill-defined. Objectives We aimed to determine the effect of C5 blockade during the effector phase on the pulmonary T H 2 response and AHR in a house dust mite (HDM) driven murine asthma model. Methods BALB/c mice were sensitized and challenged repeatedly with HDM via the airways to induce allergic lung inflammation. Sensitized mice received twice weekly injections with a blocking anti-C5 or control antibody 24 h before the first challenge. Results HDM challenge in sensitized mice resulted in elevated C5a levels in bronchoalveolar lavage fluid. Anti-C5 administered to sensitized mice prior to the first HDM challenge prevented this rise in C5a, but did not influence the influx of eosinophils or neutrophils. While anti-C5 did not impact the recruitment of CD4 T cells upon HDM challenge, it reduced the proportion of T H 2 cells recruited to the airways, attenuated IL-4 release by regional lymph nodes restimulated with HDM ex vivo and mitigated the plasma IgE response. Anti-C5 did not affect innate lymphoid cell (ILC) proliferation or group 2 ILC (ILC2) differentiation. Anti-C5 attenuated HDM induced AHR in the absence of an effect on lung histopathology, mucus production or vascular leak. Conclusions Generation of C5a during the effector phase of HDM induced allergic lung inflammation contributes to T H 2 cell differentiation and AHR without impacting ILC2 cells. Electronic supplementary material The online version of this article (10.1186/s12931-019-1136-5) contains supplementary material, which is available to authorized users.