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Host Defense Peptides (HDPs) are key components of innate immunity that exert antimicrobial, antibiofilm, and immunomodulatory activities in all higher organisms. Synthetic peptidomimetic analogs were designed to retain the desirable pharmacological properties of HDPs while having improved stability toward enzymatic degradation, providing enhanced potential for therapeutic applications. Lipidated peptide/β-peptoid hybrids [e.g., Pam-(Lys-βNspe)6-NH2 (PM1) and Lau-(Lys-βNspe)6-NH2 (PM2)] are proteolytically stable HDP mimetics displaying anti-inflammatory activity and formyl peptide receptor 2 antagonism in human and mouse immune cells in vitro. Here PM1 and PM2 were investigated for their in vivo anti-inflammatory activity in a phorbol 12-myristate 13-acetate (PMA)-induced acute mouse ear inflammation model. Topical administration of PM1 or PM2 led to attenuated PMA-induced ear edema, reduced local production of the pro-inflammatory chemokines MCP-1 and CXCL-1 as well as the cytokine IL-6. In addition, diminished neutrophil infiltration into PMA-inflamed ear tissue and suppressed local release of reactive oxygen and nitrogen species were observed upon treatment. The obtained results show that these two peptidomimetics exhibit anti-inflammatory effects comparable to that of the non-steroidal anti-inflammatory drug indomethacin, and hence possess a potential for treatment of inflammatory skin conditions.

Systemic sclerosis is a profibrotic autoimmune disease mediated by the dysregulation of extracellular matrix synthesis. Formyl peptide receptor 2 (Fpr2) is a G protein-coupled receptor that modulates inflammation and host defense by regulating the activation of inflammatory cells, such as macrophages. However, the role of Fpr2 in the development and therapy of scleroderma is still unclear. The present study was conducted to investigate the effects of Fpr2 activation in the treatment of scleroderma fibrosis. We found that intradermal administration of WKYMVm, an Fpr2-specific agonist, alleviated bleomycin-induced scleroderma fibrosis in mice and decreased dermal thickness in scleroderma skin. WKYMVm-treated scleroderma skin tissues displayed reduced numbers of myofibroblasts expressing α-smooth muscle actin, Vimentin, and phosphorylated SMAD3. WKYMVm treatment attenuated macrophage infiltration in scleroderma skin and reduced the number of M2 macrophages. The therapeutic effects of WKYMVm in scleroderma-associated fibrosis and inflammation were completely abrogated in Fpr2 knockout mice. Moreover, WKYMVm treatment reduced the serum levels of inflammatory cytokines, such as tumor necrosis factor-α, and interferon-γ, in the scleroderma model of wild-type mice but not in Fpr2 knockout mice. These results suggest that WKYMVm-induced activation of Fpr2 leads to alleviation of fibrosis by stimulating immune resolution in systemic sclerosis.

Chronic obstructive pulmonary disease (COPD) is a leading cause of disability and death world-wide, where chronic inflammation accelerates lung function decline. Pathological inflammation is worsened by chronic bacterial lung infections and susceptibility to recurrent acute exacerbations of COPD (AECOPD), typically caused by viral and/or bacterial respiratory pathogens. Despite ongoing efforts to reduce AECOPD rates with inhaled corticosteroids, COPD patients remain at heightened risk of developing serious lung infections/AECOPD, frequently leading to hospitalization and infection-dependent delirium. Here, we review emerging mechanisms into why COPD patients are susceptible to chronic bacterial infections and highlight dysregulated inflammation and production of reactive oxygen species (ROS) as central causes. This underlying chronic infection leaves COPD patients particularly vulnerable to acute viral infections, which further destabilize host immunity to bacteria. The pathogeneses of bacterial and viral exacerbations are significant as clinical symptoms are more severe and there is a marked increase in neutrophilic inflammation and tissue damage. AECOPD triggered by a bacterial and viral co-infection increases circulating levels of the systemic inflammatory marker, serum amyloid A (SAA). SAA is a functional agonist for formyl peptide receptor 2 (FPR2/ALX), where it promotes chemotaxis and survival of neutrophils. Excessive levels of SAA can antagonize the protective actions of FPR2/ALX that involve engagement of specialized pro-resolving mediators, such as resolvin-D1. We propose that the anti-microbial and anti-inflammatory actions of specialized pro-resolving mediators, such as resolvin-D1 should be harnessed for the treatment of AECOPD that are complicated by the co-pathogenesis of viruses and bacteria.

© 2018 Gouwy, De Buck, Abouelasrar Salama, Vandooren, Knoops, Pörtner, Vanbrabant, Berghmans, Opdenakker, Proost, Van Damme and Struyf. Serum amyloid A1 (SAA1) is a prototypic acute phase protein, induced to extremely high levels by physical insults, including inflammation and infection. Human SAA and its NH 2 -terminal part have been studied extensively in the context of amyloidosis. By contrast, little is known about COOH-terminal fragments of SAA. Intact SAA1 chemoattracts leukocytes via the G protein-coupled receptor formyl peptide receptor like 1/formyl peptide receptor 2 (FPR2). In addition to direct leukocyte activation, SAA1 induces chemokine production by signaling through toll-like receptor 2. We recently discovered that these induced chemokines synergize with intact SAA1 to chemoattract leukocytes in vitro and in vivo. Gelatinase B or matrix metalloproteinase-9 (MMP-9) is also induced by SAA1 during infection and inflammation and processes many substrates in the immune system. We demonstrate here that MMP-9 rapidly cleaves SAA1 at a known consensus sequence that is also present in gelatins. Processing of SAA1 by MMP-9 at an accessible loop between two alpha helices yielded predominantly three COOH-terminal fragments: SAA1(52-104), SAA1(57-104), and SAA1(58-104), with a relative molecular mass of 5,884.4, 5,327.3, and 5,256.3, respectively. To investigate the effect of proteolytic processing on the biological activity of SAA1, we chemically synthesized the COOH-terminal SAA fragments SAA1(52-104) and SAA1(58-104) and the complementary NH 2 -terminal peptide SAA1(1-51). In contrast to intact SAA1, the synthesized SAA1 peptides did not induce interleukin-8/CXCL8 in monocytes or fibroblasts. Moreover, these fragments possessed no direct chemotactic activity for neutrophils, as observed for intact SAA1. However, comparable to intact SAA1, SAA1(58-104) cooperated with CXCL8 in neutrophil activation and migration, whereas SAA1(1-51) lacked this potentiating activity. This cooperative interaction between the COOH-terminal SAA1 fragment and CXCL8 in neutrophil chemotaxis was mediated by FPR2. Hence, proteolytic cleavage of SAA1 by MMP-9 fine tunes the inflammatory capacity of this acute phase protein in that only the synergistic interactions with chemokines remain to prolong the duration of inflammation. ispartof: Frontiers In Immunology vol:9 issue:JUN ispartof: location:Switzerland status: published

In proliferative diabetic retinopathy (PDR), activated Muller glial cells (MGCs) exhibit increased motility and a fibroblast-like proliferation phenotype that contribute to the formation of fibrovascular membrane. In this study, we investigated the capacity of high glucose (HG) to regulate the expression of cell surface receptors that may participate in the proinflammatory responses of MGCs. We found that MGCs express a G-protein coupled chemoattractant receptor formyl peptide receptor 2 (Fpr2) and fibroblast growth factor receptor 1 (FGFR1), which mediated MGC migration and proliferation in response to corresponding ligands. HG upregulated Fpr2 through an NF-κB pathway in MGCs, increased the activation of MAPKs coupled to Fpr2 and FGFR1, which also further enhanced the production of vascular endothelial growth factor by MGCs in the presence of HG. In vivo, Fpr2 was more highly expressed by retina MGCs of diabetic mice and the human counterpart FPR2 was detected in the retina MGCs in fibrovascular membrane of PDR patients. To support the potential pathological relevance of Fpr2, an endogenous Fpr2 agonist cathelin-related antimicrobial peptide was detected in mouse MGCs and the retina, which was upregulated by HG. These results suggest that Fpr2, together with FGFR1, may actively participate in the pathogenesis of PDR thus may be considered as one of the potential therapeutic targets.

Most notable among the acute phase proteins is serum amyloid A (SAA), levels of which can increase 1000-fold during infections, aseptic inflammation, and/or trauma. Chronically elevated SAA levels are associated with a wide variety of pathological conditions, including obesity and rheumatic diseases. Using a recombinant hybrid of the two human SAA isoforms (SAA1 and 2) that does not exist in vivo, numerous in vitro studies have given rise to the notion that acute phase SAA is a pro-inflammatory molecule with cytokine-like properties. It is however unclear whether endogenous acute phase SAA per se mediates pro-inflammatory effects. We tested this in samples from patients with inflammatory arthritis and in a transgenic mouse model that expresses human SAA1. Endogenous human SAA did not drive production of pro-inflammatory IL-8/KC in either of these settings. Human neutrophils derived from arthritis patients displayed no signs of activation, despite being exposed to severely elevated SAA levels in circulation, and SAA-rich sera also failed to activate cells in vitro. In contrast, two recombinant SAA variants (the hybrid SAA and SAA1) both activated human neutrophils, inducing L-selectin shedding, production of reactive oxygen species, and production of IL-8. The hybrid SAA was approximately 100-fold more potent than recombinant SAA1. Recombinant hybrid SAA and SAA1 activated neutrophils through different receptors, with recombinant SAA1 being a ligand for formyl peptide receptor 2 (FPR2). We conclude that even though recombinant SAAs can be valuable tools for studying neutrophil activation, they do not reflect the nature of the endogenous protein.