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  • br Acute host defense Inflammation the host response to


    Acute host defense Inflammation, the host response to infection and tissue injury, is crucial for survival and restoration of tissue structure and function. This acute response is mediated and governed by a variety of pro-inflammatory circuits to ensure recognition of invading pathogens, coordinated recruitment of inflammatory apigenin and clearance of microbes and damaged cells from the affected site (Gilroy et al., 2004, Serhan and Savill, 2005, Ley et al., 2007, Takeuchi and Akira, 2010, Serhan, 2014). Neutralization of the offending insult ideally prompts resolution of inflammation and return to homeostasis. Resolution is an active process orchestrated by distinct cellular events and specialized pro-resolving mediators (SPMs) (Serhan, 2014). Defect in the resolution program results in persisting inflammation and collateral tissue damage that underlies many diseases (Ortega-Gomez et al., 2013, Nathan and Ding, 2010). Efficient resolution depends on inhibition of neutrophil influx, monocyte recruitment, promotion of PMN apoptosis and their clearance by macrophages via efferocytosis (Serhan and Savill, 2005, Nathan and Ding, 2010). Phagocytosis of bacteria induces PMN apoptosis (El Kebir and Filep, 2013, Mayadas et al., 2014) and apoptotic PMNs exhibit anti-inflammatory properties (Ren et al., 2008). In the inflammatory microenvironment phagocytosis of apoptotic PMNs (and other cell types) polarizes macrophages towards a pro-resolution (M2) phenotype, which facilitates tissue repair (Schif-Zuck et al., 2011, Sica and Mantovani, 2012). Studies with cultured cells, preclinical models and clinical samples have positioned formyl peptide receptors (FPRs) at pivotal checkpoints from initiation of the inflammatory response to return to homeostasis. Dysregulated or defective resolution programs are increasingly recognized as critical components of many chronic human diseases (Planaguma et al., 2008, Libby et al., 2014, Serhan, 2014, Fredman et al., 2016). Thus, therapeutic approaches to stimulate resolution and tissue repair have considerable interest and address a yet unmet clinical need.
    The Formyl peptide receptor family
    FPRs in host defense and inflammation FPR ligands are ubiquitous in the context of inflammation, function as danger signals and are highly diverse functionally (Ye et al., 2009). Not surprisingly, they govern all phases of the inflammatory response from sensing chemotactic cues through orchestrating leukocyte trafficking and clearance of inflammatory cells to tissue repair. N-formyl peptides are capable of alerting the immune system to exposure of bacteria or acute cell damage. Ligation of FPR1on myeloid cells triggers a wide variety of functions, including chemotaxis, degranulation, formation of reactive oxygen species, phagocytosis, expulsion of neutrophil extracellular traps and paracrine signaling to recruit other cell types (Ye et al., 2009, Kolaczkowska and Kubes, 2013, Dorward et al., 2015). In mouse models, Fpr1 is critical for PMN-mediated host defense against bacteria (Gao et al., 1999, Liu et al., 2012, Oldekamp et al., 2014) and host-commensal interaction during dysbiosis (Molloy et al., 2013). In a liver sterile-injury model Fpr1guides neutrophils, subsequent to other chemokine GPCRs, into the necrotic center of inflammation (McDonald et al., 2010). CHIPS secreted by S. aureus displayed potent anti-FPR1 activity (Haas et al., 2004), suggesting a potential mechanism for bacterial invasion by evading neutrophils. Many host-derived agonist peptides and lipids function as danger-associated molecular patterns for FPR2/ALX. Ligation of FPR2/ALX by different agonists often evokes opposing biological activities. For instance, SAA promotes (Badolato et al., 1994), whereas LXA4, RvD1 and AnxA1inhibit PMN activation and adhesion to the endothelium, thereby limiting their tissue accumulation (Perretti et al., 2002, Perretti and D`Acquisto, 2009). Studies with Fpr1 and Fpr2 knockout mice identified Fpr1/Fpr2-CXCR2-mediated neutrophil recruitment as one of the frontline sentinels in host defense against Listeria monocytogenes infection (Liu et al., 2012). Whether this paradigm is applicable to infection with bacteria other than Listeria remains to be investigated.