Macrophage TLR4 and PAR2 Signaling: Role in Regulating Vascular Inflammatory Injury and Repair

Abstract

Macrophages play a central role in dictating the tissue response to infection and orchestrating subsequent repair of the damage. In this context, macrophages residing in the lungs continuously sense and discriminate among a wide range of insults to initiate the immune responses important to host-defense. Inflammatory tissue injury also leads to activation of proteases, and thereby the coagulation pathway, to optimize injury and repair post-infection. However, long-lasting inflammatory triggers from macrophages can impair the lung's ability to recover from severe injury, leading to increased lung vascular permeability and neutrophilic injury, hallmarks of Acute Lung Injury (ALI). In this review, we discuss the roles of toll-like receptor 4 (TLR4) and protease activating receptor 2 (PAR2) expressed on the macrophage cell-surface in regulating lung vascular inflammatory signaling.

Keywords: PAR2; TLR4; acute lung injury; alveolar macrophages; inflammation; macrophage; vascular permeability.

Figure 1

Schematics of generation of lung resident macrophages. Based on the ontogeny of tissue resident macrophages (TRM), microglia originate directly from yolk-sac (YS) macrophages while other TRM originate from fetal liver monocytes. In the case of lungs, F4/80⁺ embryonic YS-MΦ seed the budding lung around E10.5 as primitive IMΦ. On E12, fetal liver monocytes enter the alveoli after birth and differentiate into AMΦ to regulate lung surfactant generation and host response F4/80⁺ bone marrow MΦ also arrive at the lung on E16 where they expand to form “definitive” IMΦ. IMΦ role needs to be defined but these are predicted to induce wound repair. Exact molecular control of IMΦ generation has not yet been fully deciphered.

Figure 2

Potential crosstalk models between TLR4 and PAR2. (A) PAR2 transactivation via EPCR and neutrophil elastase augments LPS-TLR4 inflammatory signaling. Tissue factor activates PAR2 via EPCR. TLR4-EPCR-mediated activation of PAR2 upregulated the expression of Peli1, Ccl22, and Malt1. Elastase secreted from neutrophils may cleave PAR2 to induce IL-12p40 generation in macrophages. Also, TLR2 and TLR3 may contribute to PAR2 regulation of TLR4 signaling. (B) PAR2 suppresses TLR4 inflammatory signaling, thereby facilitating resolution of lung injury. Thrombin secreted during TLR4-induced lung injury directly activates PAR2. PAR2 mediates the generation of cAMP, which suppresses TRPV4-induced Ca²⁺ entry. Deletion of PAR2, hence elimination of cAMP generation, fails to suppress Ca²⁺ entry via TRPV4, leading to protracted NFAT and NFκB activities, resulting in long-lasting inflammatory injury. Additionally, simultaneous activation of PAR2 and TLR4 in peritoneal macrophages enhanced IL-10 expression while the expression of TNF-α, IL-6, and IL-12p40 was decreased.