The annexin A1/FPR2 signaling axis expands alveolar macrophages, limits viral replication, and attenuates pathogenesis in the murine influenza A virus infection model

Schloer, Sebastian; Hübel, Nicole; Masemann, Dörthe; Pajonczyk, Denise; Brunotte, Linda; Ehrhardt, Christina; Brandenburg, Lars‐Ove; Ludwig, Stephan; Gerke, Volker; Rescher, Ursula

doi:10.1096/fj.201901265r

Cited by 51 publications

(42 citation statements)

References 91 publications

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“…6). This was particularly the case with FPR2, which has previously been noted in hypothalamic microglia (68), and which, in addition to binding viral peptides (see for example (60,69)), could play a role in neurodegenerative disorders, and mediate either pro-inflammatory or anti-inflammatory mechanisms (reviewed in (70)(71)(72)).…”

Section: Discussionmentioning

confidence: 85%

The hypothalamus as a hub for SARS-CoV-2 brain infection and pathogenesis

Nampoothiri

Sauvé

Ternier

et al. 2020

Preprint

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Most patients with COVID-19, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), display neurological symptoms, and respiratory failure in certain cases could be of extrapulmonary origin. Hypothalamic neural circuits play key roles in sex differences, diabetes, hypertension, obesity and aging, all risk factors for severe COVID-19, besides being connected to olfactory/gustative and brainstem cardiorespiratory centers. Here, human brain gene-expression analyses and immunohistochemistry reveal that the hypothalamus and associated regions express angiotensin-converting enzyme 2 and transmembrane proteinase, serine 2, which mediate SARS-CoV-2 cellular entry, in correlation with genes or pathways involved in physiological functions or viral pathogenesis. A post-mortem patient brain shows viral invasion and replication in both the olfactory bulb and the hypothalamus, while animal studies indicate that sex hormones and metabolic diseases influence this susceptibility. Main textSARS-CoV-2 infection is increasingly associated with a wide range of neurological symptomsheadaches, dizziness, nausea, loss of consciousness, seizures, encephalitis etc., as well as anosmia or ageusia -in the majority of patients (1,2). Additionally, many COVID-19 patients with severe disease do not respond well to artificial ventilation or display "silent hypoxia" (3), suggesting an extrapulmonary component to respiratory dysfunction, and cardiorespiratory function and fluid homeostasis are themselves subject to central nervous system (CNS) control. However, despite emerging reports of the post-mortem detection of the virus in the cerebrospinal fluid (CSF) (see for example (4)) or brain parenchyma of patients (5), little is known about how and under what circumstances SARS-CoV-2 infects the brain.While the possibility of CNS infection has been largely underestimated due to the common view that angiotensin converting enzyme 2 (ACE2), the only confirmed cellular receptor for SARS-CoV-2 so far (6), is absent or expressed only at very low levels in the brain (7,8), and that too exclusively in vascular cells (He et al., bioRxiv 2020; doi: https://doi.org/10.1101.088500) the majority of these studies have focused on the cerebral cortex, ignoring the fact that other regions such as the hypothalamus, are rich in ACE2 (9). Intriguingly, most major risk factors for severe COVID-19 (male sex, age, obesity, hypertension, diabetes); reviewed by (10,11); could be mediated by normal or dysfunctional hypothalamic neural networks that regulate a variety of physiological processes: sexual differentiation and gonadal hormone production, energy homeostasis, fluid homeostasis/osmoregulation and even ageing (12)(13)(14). The hypothalamus is also directly linked to other parts of the CNS involved in functions affected in COVID-19 patients, including brainstem nuclei that control fluid homeostasis, cardiac function and respiration, as well as regions implicated in the perception or integration of odor and taste (12,(14)(15)(16)(17)(18).Here, we inves...

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Section: Discussionmentioning

confidence: 85%

The hypothalamus as a hub for SARS-CoV-2 brain infection and pathogenesis

Nampoothiri

Sauvé

Ternier

et al. 2020

Preprint

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“…Because overactivation of the innate immune response is often correlated with excessive and deleterious tissue damage, e.g., in influenza A virus (IAV) infection, targeting the FPR family might represent a novel approach to balance innate immunity. Indeed, our previous studies revealed the advantageous use of the host-derived anti-inflammatory N-terminal annexin A1 peptide Ac-2-26, a pan-FPR agonist [46] to counteract viral load and mortality in a preclinical murine IAV infection model [47], thus encouraging the development of novel FPR-based therapies.…”

Section: Discussionmentioning

confidence: 99%

Exploring Biased Agonism at FPR1 as a Means to Encode Danger Sensing

Gröper

König

Kostenis

et al. 2020

Cells

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Ligand-based selectivity in signal transduction (biased signaling) is an emerging field of G protein-coupled receptor (GPCR) research and might allow the development of drugs with targeted activation profiles. Human formyl peptide receptor 1 (FPR1) is a GPCR that detects potentially hazardous states characterized by the appearance of N-formylated peptides that originate from either bacteria or mitochondria during tissue destruction; however, the receptor also responds to several non-formylated agonists from various sources. We hypothesized that an additional layer of FPR signaling is encoded by biased agonism, thus allowing the discrimination of the source of threat. We resorted to the comparative analysis of FPR1 agonist-evoked responses across three prototypical GPCR signaling pathways, i.e., the inhibition of cAMP formation, receptor internalization, and ERK activation, and analyzed cellular responses elicited by several bacteria-and mitochondria-derived ligands. We also included the anti-inflammatory annexinA1 peptide Ac2-26 and two synthetic ligands, the W-peptide and the small molecule FPRA14. Compared to the endogenous agonists, the bacterial agonists displayed significantly higher potencies and efficacies. Selective pathway activation was not observed, as both groups were similarly biased towards the inhibition of cAMP formation. The general agonist bias in FPR1 signaling suggests a source-independent pathway selectivity for transmission of pro-inflammatory danger signaling.Cells 2020, 9, 1054 2 of 18 translation. However, mitochondria, which are considered to represent endosymbionts of bacterial origin [3], initiate protein biosynthesis with N-formylated methionine and might release detectable levels of formylated peptides in situations of enhanced cell death or trauma [4,5]. Therefore, the appearance of N-formylated peptides signals potentially hazardous states caused by either bacterial threats (PAMPs) or tissue destruction (DAMPs).In higher eukaryotes, this unique pattern is sensed by the family of formyl peptide receptors (FPRs), which belong to the superfamily of G protein-coupled receptors (GPCRs) [5,6]. Thus, a shared sensor system detects bacteria-derived ligands and those that are liberated by non-infectious tissue destruction from mitochondria. The corresponding formylated peptides elicit strong signals via the activation of formyl peptide receptor 1 (FPR1) [7,8]. Here, we addressed whether human FPR1 is capable to decode the actual source of threat via different, i.e., ligand-specific signaling, and consequently modify the elicited cellular responses. We hypothesized that these layers of signal information are encoded by distinguishing ligand perception and potentially are governed by biased agonism. This emerging concept in GPCR-mediated signal transduction [9] emphasizes that ligands selectively stabilize specific receptor conformations that ultimately favor one (or more) signaling pathways out of the many the receptor is linked to. The final cellular response elicited by the receptor/ligand...

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“…In agreement with our results, the significant therapeutic potential of AnxA1:FPR2 was recently uncovered during a murine model of viral pneumonia. The proresolving actions of AnxA1 were shown to enhance host response during Influenza infection through the expansion of alveolar macrophages which protected mice from pathology . Collectively, our results provide evidence for the protective role of AnxA1 during respiratory infections.…”

Section: Discussionmentioning

confidence: 99%

The Annexin A1/FPR2 pathway controls the inflammatory response and bacterial dissemination in experimental pneumococcal pneumonia

et al. 2019

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Streptococcus pneumoniae is a major cause of community-acquired pneumonia leading to high mortality rates. Inflammation triggered by pneumococcal infection is necessary for bacterial clearance but must be spatially and temporally regulated to prevent further tissue damage and bacterial dissemination. Annexin A1 (AnxA1) mainly acts through Formyl Peptide Receptor 2 (FPR2) inducing the resolution of inflammation. Here, we have evaluated the role of AnxA1 and FPR2 during pneumococcal pneumonia in mice. For that, AnxA1, Fpr2/3 knockout (KO) mice and wild-type (WT) controls were infected intranasally with S pneumoniae. AnxA1 and Fpr2/3 KO mice were highly susceptible to infection, displaying uncontrolled inflammation, increased bacterial dissemination, and pulmonary dysfunction compared to WT animals. Mechanistically, the absence of AnxA1 resulted in the loss of lung barrier integrity and increased neutrophil activation upon S pneumoniae stimulation.Importantly, treatment of WT or AnxA1 KO-infected mice with Ac2-26 decreased inflammation, lung damage, and bacterial burden in the airways by increasing 2750 | MACHADO et Al.

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The annexin A1/FPR2 signaling axis expands alveolar macrophages, limits viral replication, and attenuates pathogenesis in the murine influenza A virus infection model

Cited by 51 publications

References 91 publications

The hypothalamus as a hub for SARS-CoV-2 brain infection and pathogenesis

The hypothalamus as a hub for SARS-CoV-2 brain infection and pathogenesis

Exploring Biased Agonism at FPR1 as a Means to Encode Danger Sensing

The Annexin A1/FPR2 pathway controls the inflammatory response and bacterial dissemination in experimental pneumococcal pneumonia

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