**4. Physiological roles of alveolar macrophage pro-inflammatory responses in acute LRTIs**

#### **4.1 PAMPs closely associated with activation of alveolar macrophages**

In addition to phagocytosis, alveolar macrophages induce pro-inflammatory responses by detecting PAMPs using a wide variety of PRRs, including TLRs, to facilitate the immediate mobilization and activation of phagocytes such as neutrophils and monocytes. For instance, during pulmonary infection with *S. pneumoniae*, the cell wall components of Gram-positive bacteria, lipoproteins [56], LTA [57], peptidoglycan [58], and the structural ancillary pilus protein, RrgA oligomer [59], are detected by TLR2, while the pneumococcal virulence factor pneumolysin is detected by TLR4 [60, 61]. Endopeptidase O, a new pneumococcal virulence protein, induces pro-inflammatory responses in macrophages by activating both TLR2 and TLR4 signaling [62]. For Gram-negative bacteria such as *H. influenzae* type b, the cell wall components, LPS and porin proteins, are detected by TLR4 [63] and TLR2 [64], respectively. Further, TLR9 detects bacterial DNA [65]. Thus, bacterial infection stimulates multiple TLRs simultaneously, rather than singly, resulting in complex signal activation.

#### **4.2 Downstream signaling of TLRs and their outcomes**

Detailed figures illustrating downstream signaling by TLRs are available in a highly specialized review article [5]. When TLR4 is activated by its agonists, it engages two distinct adaptor proteins in the signaling process: myeloid differentiation factor 88 (MyD88) and toll/interleukin (IL)-1 receptor domain-containing adapter-inducing interferon (IFN)-β (TRIF). The MyD88-dependent pathway recruits IL-1 receptor-associated kinases 1 and 4, which phosphorylate tumor necrosis factor (TNF) receptor-associated factor 6 (TRAF6), leading to the

#### *Physiological Role of Alveolar Macrophage in Acute Lower Respiratory Tract Infection… DOI: http://dx.doi.org/10.5772/intechopen.110509*

activation of nuclear factor-κB (NF-κB), p44/42 mitogen-activated protein kinase (MAPK), p38 MAPK, and c-Jun N-terminal kinase (JNK). However, the TRIFdependent pathway facilitates the formation of a complex consisting of TRAF3, TRAF family member-associated NF-κB activator (TANK), TANK-binding kinase 1, and inhibitor of NF-κB kinase subunit ε, which phosphorylates IFN regulatory factor 3, resulting in the activation of dimers to translocate from the cytoplasm into the nucleus. The MyD88-dependent pathway elicits the production of proinflammatory cytokines (TNF-α, IL-6, and IL-1β), chemokines (IL-8 and monocyte chemoattractant protein 1), and anti-microbial proteins (inducible nitric oxide synthase), whereas the TRIF-dependent pathway triggers the production of type I IFNs (IFN-α/β). Unlike TLR4, TLR2 and TLR9 only initiate the MyD88-dependent pathway.

#### **4.3 Roles of TLRs in pneumococcal infection**

Studies using TLR2-, TLR4-, or TLR9-knockout or mutant mice suggested the protective role of TLR2, TLR4, and TLR9 against pneumococcal infection. However, TLRs are ubiquitously expressed in cells other than immune cells. Therefore, the phenotypes observed in these studies are attributable to the lack of TLR signaling not only in alveolar macrophages but also in alveolar structural cells.

### *4.3.1 Roles of TLR2 in pneumococcal infection*

The comparison of TLR2-knockout mice with wild-type mice indicated only a partial reduction in pro-inflammatory cytokine production after intranasal *S. pneumoniae* inoculation, with no significant difference in survival rate or bacterial clearance, suggesting that TLR2 signaling plays a minor role in eliciting local inflammation and bactericidal activity against *S. pneumoniae* [66]. Further, no differences were observed between TLR2-knockout and wild-type mice in bacterial growth, lung inflammation, or pro-inflammatory cytokine and chemokine production in postinfluenza pneumococcal pneumonia [67]. Similar results were obtained in splenectomized mice [68].
