Pulmonary Innate Immune Response Determines the Outcome of Inflammation During Pneumonia and Sepsis-Associated Acute Lung Injury

Abstract

The lung is a primary organ for gas exchange in mammals that represents the largest epithelial surface in direct contact with the external environment. It also serves as a crucial immune organ, which harbors both innate and adaptive immune cells to induce a potent immune response. Due to its direct contact with the outer environment, the lung serves as a primary target organ for many airborne pathogens, toxicants (aerosols), and allergens causing pneumonia, acute respiratory distress syndrome (ARDS), and acute lung injury or inflammation (ALI). The current review describes the immunological mechanisms responsible for bacterial pneumonia and sepsis-induced ALI. It highlights the immunological differences for the severity of bacterial sepsis-induced ALI as compared to the pneumonia-associated ALI. The immune-based differences between the Gram-positive and Gram-negative bacteria-induced pneumonia show different mechanisms to induce ALI. The role of pulmonary epithelial cells (PECs), alveolar macrophages (AMs), innate lymphoid cells (ILCs), and different pattern-recognition receptors (PRRs, including Toll-like receptors (TLRs) and inflammasome proteins) in neutrophil infiltration and ALI induction have been described during pneumonia and sepsis-induced ALI. Also, the resolution of inflammation is frequently observed during ALI associated with pneumonia, whereas sepsis-associated ALI lacks it. Hence, the review mainly describes the different immune mechanisms responsible for pneumonia and sepsis-induced ALI. The differences in immune response depending on the causal pathogen (Gram-positive or Gram-negative bacteria) associated pneumonia or sepsis-induced ALI should be taken in mind specific immune-based therapeutics.

Keywords: ALI; ILCs; macrophages; neutrophils; pneumonia; sepsis.

Figure 1

Major immune cells in the mammalian lung. Lungs are potent immune organs and contain macrophages, which may be divided into alveolar macrophages (AM) and interstitial macrophages (IMs), alveolar and bronchial epithelial cells (AECs and BECs), DCs, NK cells along with other ILCs (ILC1s, ILC2s, and ILC3s), and adaptive immune cells (different T and B cells). Neutrophils also migrate to the lungs in response to the infection or inflammatory insult. Additionally, like Peyer's patches (PPs) of gut-associated lymphoid tissue (GALT), lungs also have BALT. BALT contains T cells (T cell Zone), B cells (B cell zone), and DCs. The BALT induced in response to the infection is called iBALT.

Figure 2

Overview of the bacterial pneumonia-associated innate immune response responsible for ALI. (A) Gram-negative bacterial pneumonia and ALI. The PRRs [TLRs (TLR4) and Inflammasome proteins (NLRP3)] expressed on the pulmonary innate immune cells (AECs, BECs, AMs, DCs, and NK cells) recognize Gram-negative bacteria in the lungs. This recognition induces pro-inflammatory cytokine (TNF-α, IL-6, IL-8, and IL-1β) and chemokine release. Chemokines and pro-inflammatory cytokines induce the neutrophil infiltration in the alveoli from the pulmonary blood capillaries through their vascular endothelium via diapedesis. The infiltrated neutrophils help in the pathogen clearance but also cause bystander inflammatory pulmonary tissue damage via damaging PECs or AECs. In the severe pneumonia-associated ALI, the vascular leakage of proteins and erythrocytes also occurs in the lungs. The pulmonary NK cells also release IFN-γ, which further enhances neutrophil infiltration and ALI. However, the increase in ILC3s at later stages increases the IL-17 level. This cytokine helps in the increased phagocytosis of the pathogen and the resolution of the Gram-negative bacterial pneumonia-induced ALI. (B) Gram-positive bacterial pneumonia-associated ALI. The recognition of the Gram-positive bacteria (S. aureus) induces the increased the production of chemokines and pro-inflammatory cytokines (TNF-α, IL-1β, IL-6, and IL-8), which via binding to the corresponding receptors (CXCR2) on the neutrophils induce their diapedesis to the lung alveoli from the pulmonary vascular endothelium. Neutrophils, along with bacterial clearance, also cause ALI. Pulmonary vascular endothelium damage also causes vascular leakage. The Pulmonary NK cells via their NCR1 interact with AMs to further increase the pro-inflammatory cytokine release, which further aggravates the neutrophil infiltration, pathogen clearance, and ALI also. The NLRP3 also works independently of inflammasome activation via inducing the release of TFF2 and ITLN-1. TFF2 inhibits ALI and helps in its resolution, whereas ITLN-1 clears the infection via increasing the pathogen phagocytosis. The CCL20 released from AECs increases the pulmonary ILC3 numbers, which release IL-22 that inhibits ALI and helps in its resolution.

Figure 3

Overview of sepsis-induced ALI. Local infections of the skin (S. aureus), lungs (pneumonia), and intestinal commensal bacteria leak into the blood may lead to sepsis development. Sepsis leads to the neutrophil and monocyte infiltration in the lung alveoli via pulmonary transendothelial migration due to the profound release of the pro-inflammatory mediators (cytokine storm) damaging endothelial monolayer and inducing endothelial vascular leakage. These neutrophils and monocytes reach into the lung alveoli through crossing the pulmonary epithelial layer due to damage of PECs (AECs and BECs). These PECs express C5aR and C3aR receptors. The profound release of complement component C5a during sepsis induces the inflammatory damage, and the death of PECs during sepsis causes sepsis-associated ALI. The PECs death/damage increases the SP-D, but Vwf levels decrease. The increase in the IL-10 levels in the lungs at later stages of sepsis impairs the bactericidal action of AMs along with inducing a defective efferocytosis. The defective efferocytosis among AMs further increases the ALI. The necrotic death of AMs (indicated by the cytosolic HMG-B1) at later stages of sepsis further aggravates the ALI. The neutrophils infiltrated into the lung alveoli during sepsis are apoptosis-resistant and aggravate the ALI due to their increased pro-inflammatory action on lung tissues. B1a cells inhibit neutrophil infiltration and, thus, the sepsis-induced ALI. The increase in pulmonary ILC2s also occurs.