Interleukin-1β Regulates CXCL8 Release and Influences Disease Outcome in Response to Streptococcus pneumoniae, Defining Intercellular Cooperation between Pulmonary Epithelial Cells and Macrophages

Abstract

The success of Streptococcus pneumoniae (the pneumococcus) as a pulmonary pathogen is related to its restriction of innate immune responses by respiratory epithelial cells. The mechanisms used to overcome this restriction are incompletely elucidated. Pulmonary chemokine expression involves complex cellular and molecular networks, involving the pulmonary epithelium, but the specific cellular interactions and the cytokines that control them are incompletely defined. We show that serotype 2 or 4 pneumococci induce only modest levels of CXCL8 expression from epithelial cell lines, even in the absence of a polysaccharide capsule. In contrast, coculture of A549 cells with the macrophage-like THP-1 cell line, differentiated with vitamin D, or monocyte-derived macrophages enhanced CXCL8 release. Supernatants from the THP-1 cell line prime A549 cells to release CXCL8 at levels similar to cocultures. Interleukin-1Ra (IL-1Ra) inhibits CXCL8 release from cocultures and reduces the activity of macrophage-conditioned media, but inhibition of tumor necrosis factor alpha (TNF-␣) had only a minimal effect on CXCL8 release. Release of IL-1␤ but not TNF-␣ was upregulated in cocultures. IL-1 type 1 receptor knockout C57BL/6 and BALB/c mice confirmed the importance of IL-1 signaling in CXC chemokine expression and neutrophil recruitment in vivo. In fulminant disease, increased IL-1 signaling resulted in increased neutrophils in the airway and more invasive disease. These results demonstrate that IL-1 is an important component of the cellular network involving macrophages and epithelial cells, which facilitates CXC chemokine expression and aids neutrophil recruitment during pneumococcal pneumonia. They also highlight a potential clinical role for anti-IL-1 treatment to limit excessive neutrophilic inflammation in the lung.

Distinct Contributions of Interleukin-1α (IL-1α) and IL-1β to Innate Immune Recognition of Pseudomonas aeruginosa in the Lung

“…These include extracellular pathogens, such as Streptococcus pneumoniae, Staphylococcus aureus, and Klebsiella pneumoniae (38)(39)(40), as well as intracellular bacteria, e.g., Listeria monocytogenes and Mycobacterium tuberculosis (41)(42)(43). Many papers describe the interaction of these pathogens with inflammasomes and the subsequent generation of IL-1␤ signals; these are summarized in recent reviews (44,45).…”

Alveolar macrophages in pulmonary host defence – the unrecognized role of apoptosis as a mechanism of intracellular bacterial killing

“…Macrophages are key orchestrators of inflammatory responses in the lung. They produce key regulatory cytokines, such as IL-1β, which helps to prime release of the neutrophil chemokine CXCL8 from epithelial cells [35]. They also help to induce apoptosis in target cells such as monocytes, and efferocytosis of these apoptotic cells helps to down-regulate the proinflammatory cytokine network [36,37].…”

Pulmonary immune response to Streptococcus pneumoniae

“…Activation of epithelial PRRs can contribute towards the inflammatory response to S. pneumoniae (18). However, epithelial pro-inflammatory responses can be indirectly increased by macrophages (19). This suggests that alveolar macrophages are likely to be the cell type that primarily recognise S. pneumoniae, and then stimulate the alveolar epithelium by paracrine or juxtacrine mechanisms to amplify the inflammatory response, and attract required additional cells such as neutrophils to the site of infection.…”

“…However, when large numbers of S. pneumoniae reach the lung they overwhelm alveolar macrophage mediated clearance. In response, alveolar macrophages initiate an inflammatory response through the release of pro-inflammatory cytokines including TNF, IL6, and IL-1β and chemokines (19,28), thereby recruiting additional mechanisms of microbial clearance, such as neutrophils, to the lung. Conversely, anti-inflammatory cytokines released by alveolar macrophages are necessary for resolution of inflammation (29).…”