PMC:7572937 / 21682-29336
Annnotations
{"target":"https://pubannotation.org/docs/sourcedb/PMC/sourceid/7572937","sourcedb":"PMC","sourceid":"7572937","source_url":"https://www.ncbi.nlm.nih.gov/pmc/7572937","text":"FPR2 in the respiratory tract\nFPR2 is expressed in nasal epithelial cells, bronchial epithelial cells, and BALF cells55–57. As FPR2 can detect diverse ligands, many reports have demonstrated the functional roles of FPR2 in the airway. FPR2-related airway diseases and conditions include allergic inflammation, acute lung injury (ALI), lung injury induced by fat embolism syndrome, acute respiratory distress syndrome, ventilator-induced lung injury, asthma, aspirin-exacerbated respiratory disease (AERD), and COPD55,58–64. FPR2 can be protective or harmful depending on various disease conditions.\nThe protective role of FPR2 in respiratory diseases mainly occurs with lipid-derived mediators such as RvD1 and LXA4. RvD1 is a docosahexaenoic acid-derived anti-inflammatory mediator and a ligand of FPR265. In an ALI model, pretreatment with RvD1 was found to attenuate disease onset by decreasing NF-κB nuclear translocation, MAPK signaling, proinflammatory cytokine production, and immune cell recruitment. These beneficial effects of RvD1 on ALI are dependent on FPR2 signaling and are reversed by FPR2 antagonist (BOC-2) administration65. In addition to protective effects, RvD1 has therapeutic effects against persistent ALI via the same mechanisms. In acute respiratory distress syndrome, the primary protective mechanism of RvD1 is mediated by increasing the expression of prostaglandin-producing cyclooxygenase 2 in an FPR2-dependent manner60.\nLXA4, another lipid mediator ligand of FPR2, can decrease TNF-α-induced IL-8 secretion via FPR2 signaling in bronchial epithelial cells56. In patients with rhinosinusitis, an upper airway inflammatory disease, the levels of both LXA4 and FPR2 are increased compared to those in healthy controls, accompanied by augmented defense activity. LXA4 can also decrease TNF-α-induced IL-8 secretion in nasal epithelial cells via FPR255. There are several reports regarding LXA4-FPR2 expression in asthma patients. LXA4 and FPR2 levels are increased in patients with moderate asthma but are significantly decreased in patients with severe asthma. LXA4 decreases leukocyte migration, eotaxin levels, and the production of type 2 cytokines such as IL-5 and IL-1357,62,66–68.\nSynthetic agonists of FPR2 also protect the airway from inflammation. WKYMVm blocks DC migration to the mucosa and adjacent lymph nodes and inhibits proinflammatory cytokine production, which results in a decrease in Th1 and Th17 responses in asthma69. BML-111, another synthetic agonist of FPR2, has a therapeutic effect on ventilator-induced lung injury and lung injury induced by fat embolism syndrome. This compound inhibits leukocyte migration into BALF, production of proinflammatory cytokines, and NF-κB activation59,61.\nHarmful effects of FPR2 have been reported in several respiratory pathologies, such as allergic inflammation, airway contraction, AERD, COPD, and infection. In the case of allergic inflammation, Fpr2 knockout mice show attenuated inflammation. The dominant phenotypes of Fpr2 knockout mice in allergic inflammation are a reduction in DC migration into the mucosa, a decreased in Th2 responses, and immunoglobulin production70. In allergic airway inflammation, monocyte-derived DCs are recruited to the perivascular region adjacent to the inflamed area in a CCR2-dependent manner. However, the migration of monocyte-derived DCs into the mucosa is dependent on CRAMP-FPR2 signaling71.\nRespiratory failure due to lung damage is accompanied by airway contraction, which can be induced by various damage-associated molecular patterns, among which mitochondrial N-formyl peptides act via FPR272. AERD is another disease in which the overactivated LXA4/FPR2 pathway exacerbates the pathogenesis. Because AERD is associated with arachidonic acid metabolism, the role of FPR2 in recognizing LXA4 is important in regulating AERD progression. Single-nucleotide polymorphism analyses have been conducted in AERD patients, showing that these patients have a high frequency of homozygote of the minor allele, FPR2-4509T\u003eG. This minor allele is correlated with higher FPR2 levels in CD14+ monocytes, and carriers show defective lung function upon aspirin challenge63.\nIn COPD, the balance of protective or harmful FPR2 ligands is essential. The protective FPR2 ligands with elevated levels in COPD are AnxA1, LXA4, and RvD1, and the harmful FPR2 ligands are mitochondrial formylated peptides, LL-37, and serum amyloid A (SAA)64 (Fig. 2b). The expression of FPR2 is decreased in neutrophils and T cells in COPD patients, and serum AnxA1 levels are decreased53. LXA4 treatment can block the proinflammatory response in COPD. However, proinflammatory ligands such as SAA are produced at much higher levels in the disease state, and FPR2-mediated activity therefore leads to inflammatory responses73. The primary pathological feature of COPD is neutrophilic inflammation. However, glucocorticosteroids, which are currently used as therapeutic agents for COPD, fail to alleviate neutrophilic inflammation, because glucocorticosteroids induce SAA production64. The levels of SAA in serum and BALF are high in COPD patients, and the environment of epithelial cells is rich in SAA73. SAA induces the expression of Il8 and Cxcl1/2 and the production of proinflammatory cytokines in BALF cells. Among these cytokines, IL-17A, produced by Th17 cells, γδ T cells, and epithelial cells, maintains pulmonary neutrophilic inflammation74. LL-37 is an FPR2 ligand that plays a deleterious role in COPD. LL-37 is highly expressed in the epithelium of COPD patients, and the expression level of LL-37 positively correlates with lung structural changes such as airway wall thickness and collagen deposition. The harmful effects of LL-37 are mediated by FPR2 activation in human lung fibroblasts, promoting the production of collagen75.\nFPR2 has dual effects on airway infection. Regarding bacterial infection, Fpr2/3 knockout mice and AnxA1 knockout mice are more susceptible to Streptococcus pneumoniae infection than wild-type mice. These knockout mice show decreased levels of tight junction proteins (ZO-1 and claudins), disrupted macrophage phagocytosis and uncontrolled inflammation, resulting in pulmonary dysfunction76. The results suggest that FPR2/3 are crucial for Streptococcus pneumoniae defense. However, the opposite functional activity of FPR was reported in the Klebsiella pneumoniae infection-induced sepsis model. In the early stage of pneumosepsis, the expression of LXA4 and FPR2 is elevated and causes defective bacterial clearance. FPR2 antagonist treatment reverses the effect of LXA4/FPR2 by inducing leukocyte migration into the infection site and increasing bacterial killing. However, in the late stage of pneumosepsis, LXA4/FPR2 participate in the resolution of inflammation, influencing mortality77 (Fig. 2c). Maintaining the balance between benefit and harm is important for an effective response to bacterial infection. Viruses often manipulate FPR2 signaling to escape immune clearance by exploiting its anti-inflammatory properties. Influenza A virus (IAV) is an example of a virus that uses this strategy. TLR3 expressed in innate immune cells and other cell types recognizes IAV and induces the production of type 1 interferons. The produced interferons activate STAT3, which increases the transcription of FPR2. Upregulated FPR2 carries out its anti-inflammatory functions and subsequently facilitates viral replication78. AnxA1 is incorporated into IAV particles, eliciting the activity of the FPR2-ERK-dependent pathway to play a deleterious role in host defense activity against IAV infection79 (Fig. 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