Biology subjects

Serhan, C. N.

Publications and source records attributed to Serhan, C. N..

6 recordsLinked to original sources

bioRxiv2026

MAPKAP Kinase-2 signaling enhances the resolution of colonic inflammation through specialized pro-resolving mediators

Failure to resolve acute inflammation contributes to chronic inflammatory diseases, including inflammatory bowel disease, and inflammation associated cancer. MAPKAP kinase-2 (MK2), a stress-activated effector of p38MAPK, is best known for promoting onset and amplification of inflammation through post-transcriptional regulation of cytokines. Here we identify an unexpected role for MK2 in coordinating resolution of intestinal inflammation. Following dextran sodium sulfate induced colonic injury, MK2 deficient mice developed more severe, persistent inflammation, with sustained proinflammatory cytokine and chemokine production, prolonged neutrophil accumulation, and impaired macrophage recruitment during recovery. Myeloid-restricted MK2 deficiency recapitulated the impaired resolution phenotype. Lipid mediator metabololipidomics revealed MK2 deficient colons failed to undergo the transition from pro-inflammatory to pro-resolving lipid mediator production, exhibiting markedly reduced levels of specialized pro-resolving mediators (SPMs), including resolvins and lipoxins. Exogenous SPM administration during the recovery phase restored inflammation resolution in MK2 deficient mice, improving weight, disease activity, and mucosal healing. These findings establish a previously unrecognized role for MK2 in coordinating the transition from inflammatory injury to resolution and repair. Together with our prior finding that myeloid MK2 deficiency reduces colitis-associated tumor progression, these results suggest that inflammation associated tumorigenesis depends not simply on inflammatory injury, but on its coupling to the resolution and tissue repair that follows.

systems biology↗

bioRxiv2025

Protectin DX resolves fracture-induced postoperative pain in mice via neuronal signaling and GPR37-activated macrophage efferocytosis

Protectin DX (PDX) is a member of the superfamily of specialized pro-resolving mediators (SPMs) and exerts anti-inflammatory actions in animal models; but the specific signaling pathways involved in its actions have not been fully elucidated. Here we demonstrate the analgesic actions of PDX in a mouse model of tibial fracture-induced postoperative pain (fPOP) via activation of GPR37. Intravenous early-phase and late-phase treatment of PDX (100 ng/mouse) effectively alleviated fPOP. Compared to protectin D1/neuroprotectin D1, DHA, steroid, and meloxicam, PDX produced superior pain relief. While dexamethasone and meloxicam prolonged fPOP, PDX shortened the pain duration. The analgesic effects of PDX were abrogated in Gpr37-/- mice, which displayed deficits in fPOP resolution. PDX binds GPR37 and induces calcium responses in peritoneal macrophages. LC-MS-MS-based lipidomic analysis revealed that endogenous PDX levels were [~]10-fold higher than PD1 in muscle at the fracture site. PDX promotes macrophage polarization via GPR37-dependent phagocytosis and efferocytosis through calcium signaling in vitro, and it further enhances macrophage viability and efferocytosis in vivo via GPR37. Finally, PDX rapidly modulates nociceptor neuron responses by suppressing C-fiber-induced muscle reflex in vivo and calcium responses in DRG neurons ex vivo and reducing TRPA1/TRPV1-induced acute pain and neurogenic inflammation in vivo. Our findings highlight multiple benefits of PDX to manage postoperative pain and promote perioperative recovery.

neuroscience↗

bioRxiv2022

Evidence for the presence and diagnostic utility of SPM in human peripheral blood

We thank ODonnell et al, for their comments on our contribution and are grateful to be afforded this opportunity to formally respond to their critique24. We are surprised by the authors assertion relating to the biological relevance of SPM because a simple literature search for related terms such as resolvin in PubMed yields an abundance (>1,420 publications) of evidence supporting the potent biological activities and the diagnostic potential of some of these mediators. Several co-authors of the ODonnells et al manuscript, have published on the resolvins and SPMs, including some publications within recent weeks. Importantly, ODonnell et al, misreport as well as mis-apply criteria for peak identification reported in the Gomez et al, publication which lead to the flawed analysis they performed. In this response therefore, we provide a step-by-step clarification of the methodologies used in Gomez et al, and a side-by-side comparison of the underlying data to clarify any confusion. We also demonstrate that using the orthogonal criteria discussed by ODonnell et al, we obtain essentially identical results thus providing additional validation of our techniques and support the conclusions.

immunology↗

bioRxiv2020

The Atlas of Inflammation-Resolution (AIR)

Acute inflammation is a protective reaction by the immune system in response to invading pathogens or tissue damage. Ideally, the response should be localized, self-limited, and returning to homeostasis. If not resolved, acute inflammation can result in organ pathologies leading to chronic inflammatory phenotypes. Acute inflammation and inflammation resolution are complex coordinated processes, involving a number of cell types, interacting in space and time. The biomolecular complexity and the fact that several biomedical fields are involved, make a multi and interdisciplinary approach necessary. This Atlas of Inflammation Resolution (AIR) is a web-based resource capturing the state-of-the-art in acute inflammation and inflammation resolution research. The AIR provides an interface for users to search thousands of interactions, arranged in inter-connected multi-layers of process diagrams, covering a wide range of clinically relevant phenotypes. The AIR serves as an open access knowledgebase, including a gateway to numerous public databases. It is furthermore possible for the user to map experimental data onto the molecular interaction maps of the AIR, providing the basis for bioinformatics analyses and systems biology approaches. By mapping experimental data onto the Atlas, it can be used to elucidate drug action as well as molecular mechanisms underlying different disease phenotypes. For the visualization and exploration of information, the AIR uses the Minerva platform, which is a well-established tool for the presentation of disease maps. The molecular details of the AIR are encoded using international standards. The Atlas of Inflammation Resolution was created as a freely accessible resource, supporting research and education in the fields of acute inflammation and inflammation resolution. The AIR connects research communities, facilitates clinical decision making, and supports research scientists in the formulation and validation of hypotheses.

immunology↗

bioRxiv2019

Resolvin D-series regulates Phospholipase D both during inflammation and resolution by modulating phagocyte functions

A successful acute inflammatory response results in the elimination of infectious agents by neutrophils and monocytes, followed by resolution and repair by tissue-resident and recruited macrophages. D-series resolvins are pro-resolving mediators involved in resolution and tissue repair, their intracellular signaling mechanism(s) are of interest. Here, we report that D-series resolvins activate phospholipase D (PLD), a ubiquitously expressed membrane lipase in modulating phagocyte functions. The mechanism for PLD-mediated actions of RvD5 in polarizing macrophages (M1-M2) was found to be two-pronged: (a) RvD5 inhibits post-transcriptional modifications, by miRs and 3exonulceases that process PLD2 mRNA, thus increasing PLD2 expression and activity; (b) RvD5 enhances PLD2-S6K signaling and Actin expression required for membrane expansion and efferocytosis. In addition, investigating RvD5s actions in second organ reflow injury, we found that RvD5 did not reduce lung neutrophil myeloperoxidase levels in PLD2-/- mice compared to WT and PLD1-/- mice, pointing to a unique role of PLD2 as the relevant isoform in RvD5-mediated resolution. These results demonstrate that RvD5-PLD2 are attractive targets for therapeutic interventions in vascular inflammation such as I/R injury and cardiovascular diseases.

immunology↗

bioRxiv2018

Specific Oxylipins Enhance Vertebrate Hematopoiesis via the Receptor GPR132

Epoxyeicosatrienoic acids (EETs) are endogenous lipid signaling molecules with cardioprotective and vasodilatory actions. We recently showed that exogenous addition of 11,12-EET enhances hematopoietic induction and engraftment in mice and zebrafish. EETs are known to signal via a G-protein coupled receptor(s), and significant research supports the existence of a specific high-affinity receptor. Identification of a hematopoietic specific EET receptor would enable genetic interrogation of the EET signaling pathway and perhaps clinical use of this molecule. We developed a bioinformatic approach to identify the EET receptor based on the expression of GPCRs in cell lines with differential responses to EETs. We found 10 candidate EET receptors that are commonly expressed in three EET-responsive human cell lines, but not expressed in an EET-unresponsive line. Of these candidates, only GPR132 showed EET-responsiveness in vitro using a luminescence-based assay for {beta}-arrestin recruitment. Knockdown of zebrafish gpr132b prevented EET-induced hematopoiesis, and marrow from GPR132 knockout mice showed decreased long-term engraftment capability. In contrast to the putative high-affinity EET receptor, GPR132 is reported to have affinity for additional fatty acids in vitro, and we found that these same fatty acids enhance hematopoietic stem cell specification in the zebrafish. We conducted structure-activity relationship analyses using both in vitro and in vivo assays on diverse medium chain fatty acids. Certain oxygenated, unsaturated free fatty acids showed high activation of GPR132, while unoxygenated or saturated fatty acids had lower activity. Absence of the carboxylic acid moiety prevented activity, suggesting that this moiety is required for receptor activation. GPR132 responds to a select panel of polyunsaturated, oxygenated fatty acids to enhance both embryonic and adult hematopoiesis.

developmental biology↗