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Vascular permeability is temporarily heightened during inflammation, but excessive inflammation‐associated microvascular leakage can be detrimental, as evidenced in the inflamed lung. Formylated peptides regulate vascular leakage indirectly via formylated peptide receptor‐1 (FPR1)‐mediated recruitment and activation of neutrophils. Here we identify how the GTPase‐activating protein ARAP3 protects against formylated peptide‐induced microvascular permeability via endothelial cells and neutrophils. In vitro, Arap3−/− endothelial monolayers were characterised by enhanced formylated peptide‐induced permeability due to upregulated endothelial FPR1 and enhanced vascular endothelial cadherin internalisation. In vivo, enhanced inflammation‐associated microvascular leakage was observed in Arap3−/− mice. Leakage of plasma protein into the lungs of Arap3−/− mice increased within hours of formylated peptide administration. Adoptive transfer experiments indicated this was dependent upon ARAP3 deficiency in both immune and non‐immune cells. Bronchoalveolar lavages of formylated peptide‐challenged Arap3−/− mice contained neutrophil extracellular traps (NETs). Pharmacological inhibition of NET formation abrogated excessive microvascular leakage, indicating a critical function of NETs in this context. The observation that Arap3−/− mice developed more severe influenza suggests these findings are pertinent to pathological situations characterised by abundant formylated peptides. © 2024 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland. [ABSTRACT FROM AUTHOR]

Increased levels of tumor‐associated macrophages (TAMs) are indicators of poor prognosis in most cancers. Although antibodies and small molecules blocking the recruitment of macrophages to tumors are under evaluation as anticancer therapies, these strategies are not specific for macrophage subpopulations. Herein we report the first enzyme‐activatable chemokine conjugates for effective targeting of defined macrophage subsets in live tumors. Our constructs exploit the high expression of chemokine receptors (e.g. CCR2) and the activity of cysteine cathepsins in TAMs to target these cells selectively over other macrophages and immune cells (e.g. neutrophils, T cells, B cells). Furthermore, we demonstrate that cathepsin‐activatable chemokines are compatible with both fluorescent and therapeutic cargos, opening new avenues in the design of targeted theranostic probes for immune cells in the tumor microenvironment. [ABSTRACT FROM AUTHOR]

Rheumatoid arthritis (RA) is a chronic, systemic autoimmune disease without known cure that primarily affects synovial joints. RA has a prevalence of approximately 1% of the population worldwide. A vicious circle between two critical immune cell types, B cells and neutrophils, develops and promotes disease. Pathogenic anti‐citrullinated protein antibodies (ACPA) directed against a range of citrullinated epitopes are abundant in both plasma and synovial fluid of RA patients. In addition to stimulating numerous cell types, ACPA and other autoantibodies, notably rheumatoid factor, form immune complexes (ICs) that potently activate neutrophils. Attracted to the synovium by abundant chemokines, neutrophils are locally stimulated by ICs. They generate cytokines and release cytotoxic compounds including neutrophil extracellular traps (NETs), strands of decondensed chromatin decorated with citrullinated histones and granule‐derived neutrophil proteins, which are particularly abundant in the synovial fluid. In this way, neutrophils generate citrullinated epitopes and release peptidylarginine deiminase (PAD) enzymes capable of citrullinating extracellular proteins in the rheumatic joint, contributing to renewed ACPA generation. This review article focusses on the central function of citrullination, a post‐translational modification of arginine residues in RA. The discussion includes ACPA and related autoantibodies, somatic hypermutation‐mediated escape from negative selection by autoreactive B cells, promotion of the dominance of citrullinated antigens by genetic and lifestyle susceptibility factors and the vicious circle between ACPA‐producing pathogenic B cells and NET‐producing neutrophils in RA. [ABSTRACT FROM AUTHOR]

Neutrophils, the most abundant circulating leukocytes in humans have key roles in host defense and in the inflammatory response. Agonist-activated phosphoinositide 3-kinases (PI3Ks) are important regulators of many facets of neutrophil biology. PIP3 is subject to dephosphorylation by several 5' phosphatases, including SHIP family phosphatases, which convert the PI3K product and lipid second messenger phosphatidylinositol 3,4,5-trisphosphate (PIP3) into PI(3,4)P2, a lipid second messenger in its own right. In addition to the leukocyte restricted SHIP1, neutrophils express the ubiquitous SHIP2. This study analyzed mice and isolated neutrophils carrying a catalytically inactive SHIP2, identifying an important regulatory function in neutrophil chemotaxis and directionality in vitro and in neutrophil recruitment to sites of sterile inflammation in vivo , in the absence of major defects of any other neutrophil functions analyzed, including, phagocytosis and the formation of reactive oxygen species. Mechanistically, this is explained by a subtle effect on global 3-phosphorylated phosphoinositide species. This work identifies a non-redundant role for the hitherto overlooked SHIP2 in the regulation of neutrophils, and specifically, neutrophil chemotaxis/trafficking. It completes an emerging wider understanding of the complexity of PI3K signaling in the neutrophil, and the roles played by individual kinases and phosphatases within. [ABSTRACT FROM AUTHOR]

The cholinergic anti-inflammatory pathway (CAP) is an innate neural reflex where parasympathetic and sympathetic nerves work jointly to control inflammation. Activation of CAP by vagus nerve stimulation (VNS) has paved way for novel therapeutic strategies in treating inflammatory diseases. Recently, we discovered that VNS mediated splenic acetylcholine (ACh) release and subsequent immunosuppression in response to LPS associated inflammation is impaired in mice lacking microsomal prostaglandin E synthase-1 (mPGES-1) expression, a key enzyme responsible for prostaglandin E2 synthesis. Here, we have further investigated the consequences of mPGES-1 deficiency on various molecular/cellular events in the spleen which is critical for the optimal functioning of VNS in endotoxaemic mice. First, VNS induced splenic norepinephrine (NE) release in both mPGES-1 (+/+) and (-/-) mice. Compared to mPGES-1 (+/+), immunomodulatory effects of NE on cytokines were strongly compromised in mPGES-1 (-/-) splenocytes. Interestingly, while LPS increased choline acetyltransferase (ChAT) protein level in mPGES-1 (+/+) splenocytes, it failed to exert similar effects in mPGES-1 (-/-) splenocytes despite unaltered β2 AR protein expression. In addition, nicotine inhibited TNFα release by LPS activated mPGES-1 (+/+) splenocytes in vitro. However, such immunosuppressive effects of nicotine were reversed both in mPGES-1 (-/-) mouse splenocytes and human PBMC treated with mPGES-1 inhibitor. In summary, our data implicate PGE2 as an important mediator of ACh synthesis and noradrenergic/cholinergic molecular events in the spleen that constitute a crucial part of the CAP immune regulation. Our results suggest a possible link between cholinergic and PG system of CAP that may be of clinical significance in VNS treatment. [ABSTRACT FROM AUTHOR]

Neutrophils are amongst the first cells to be recruited to sites of infection or trauma. Neutrophil functional responsiveness is tightly regulated by many agents including immune complexes. These immune cells can generate reactive oxygen species and degranulate to release abundant cytotoxic products, making them efficient at killing invading microorganisms. If neutrophil function is dysregulated, however, these cells have the potential to cause unwanted host tissue damage as exemplified by pathological and chronic inflammatory conditions. In physiological inflammation, once the initial insult has efficiently been dealt with, neutrophils are thought to leave the tissues or undergo programmed cells death, especially apoptosis. Apoptotic neutrophils are then rapidly removed by other phagocytes, primarily macrophages, by mechanisms that do not elicit a pro‐inflammatory response. In this review, we discuss the interesting observations and consequences that immune complexes have on neutrophil cell death processes such as apoptosis. [ABSTRACT FROM AUTHOR]

Photocatalysts are excellent scaffolds for the light-mediated control of bioactive molecules. Current photocatalytic structures are not compatible with genetic encoding and therefore cannot be directly incorporated into the sequences of native proteins. Herein, we developed new amino acids incorporating Si-rosamine photocatalytic units, and introduced them via aminoacylation of tRNAs into specific positions of different proteins to enable targeted photocatalytic reactions in defined populations of immune cells., Competing Interests: There are no conflicts to declare., (This journal is © The Royal Society of Chemistry.)

Galectin (Gal)-3 is a profibrotic β-galactoside-binding lectin that plays a key role in the pathogenesis of idiopathic pulmonary fibrosis (IPF) and IPF exacerbations. TD139 is a novel and potent small-molecule inhibitor of Gal-3.A randomised, double-blind, multicentre, placebo-controlled, phase 1/2a study was conducted to assess the safety, tolerability, pharmacokinetics and pharmacodynamics of inhaled TD139 in 36 healthy subjects and 24 patients with IPF. Six dose cohorts of six healthy subjects were evaluated (4:2 TD139:placebo ratio) with single doses of TD139 (0.15-50 mg) and three dose cohorts of eight patients with IPF (5:3 TD139:placebo ratio) with once-daily doses of TD139 (0.3-10 mg) for 14 days.Inhaled TD139 was well tolerated with no significant treatment-related side-effects. TD139 was rapidly absorbed, with mean time taken to reach maximum plasma concentration ( C max ) values ranging from 0.6 to 3 h and a plasma half-life ( T 1/2 ) of 8 h. The concentration of TD139 in the lung was >567-fold higher than in the blood, with systemic exposure predicting exposure in the target compartment. Gal-3 expression on alveolar macrophages was reduced in the 3 and 10 mg dose groups compared with placebo, with a concentration-dependent inhibition demonstrated. Inhibition of Gal-3 expression in the lung was associated with reductions in plasma biomarkers centrally relevant to IPF pathobiology (platelet-derived growth factor-BB, plasminogen activator inhibitor-1, Gal-3, CCL18 and YKL-40).TD139 is safe and well tolerated in healthy subjects and IPF patients. It was shown to suppress Gal-3 expression on bronchoalveolar lavage macrophages and, in a concerted fashion, decrease plasma biomarkers associated with IPF progression., Competing Interests: Conflict of interest: N. Hirani reports grants from Galecto Biotech, during the conduct of the study. Conflict of interest: A.C. MacKinnon reports personal fees from Galecto Biotech, outside the submitted work; and has a patent CA2,794,066 issued, a patent US13/832,672 issued and a patent WO/2014/067986 pending (all patents are fully owned by Galecto Biotech). Conflict of interest: L. Nicol reports grants from Galecto Biotech, during the conduct of the study; personal fees for lectures from Boehringer Ingelheim, outside the submitted work. Conflict of interest: P. Ford reports personal fees and nonfinancial support from Galecto, during the conduct of the study; and has a patent TD139 issued. Conflict of interest: H. Schambye reports personal fees from Galecto Inc, outside the submitted work; and has a patent WO/2016/180483 pending (fully owned by Galecto Biotech). Conflict of interest: A. Pedersen reports personal fees from Galecto Biotech, outside the submitted work. Conflict of interest: U.J. Nilsson has a patent CA2,794,066 issued, a patent US13/832,672 issued, a patent WO/2014/067986 pending, a patent WO/2005/113569 pending and a patent WO/2009/139719 pending (all patents are fully owned by Galecto Biotech). Conflict of interest: H. Leffler has a patent CA2,794,066 issued, a patent US13/832,672 issued, a patent WO/2014/067986 pending and a patent WO/2005/113569 pending (all patents are fully owned by Galecto Biotech). Conflict of interest: T. Sethi reports personal fees from Galecto Biotech, outside the submitted work; and has a patent CA2,794,066 issued, a patent US13/832,672 issued and a patent WO/2014/067986 pending (patents are fully owned by Galecto Biotech). Conflict of interest: S. Tantawi reports personal fees from Galecto Biotech, outside the submitted work. Conflict of interest: L. Gravelle reports personal fees from Galecto Biotech, outside the submitted work; and has a patent WO/2017/103109 pending (fully owned by Galecto Biotech). Conflict of interest: R.J. Slack reports personal fees from Galecto Biotech, outside the submitted work. Conflict of interest: R. Mills has nothing to disclose. Conflict of interest: U. Karmakar has nothing to disclose. Conflict of interest: D. Humphries has nothing to disclose. Conflict of interest: F. Zetterberg reports personal fees from Galecto Biotech, outside the submitted work. Conflict of interest: L. Keeling has nothing to disclose. Conflict of interest: L. Paul has nothing to disclose. Conflict of interest: P.L. Molyneaux has, via his institution, received industry-academic funding from AstraZeneca and has received speaker and consultancy fees from Boehringer Ingelheim and Hoffman-La Roche, outside the submitted work. Conflict of interest: F. Li has nothing to disclose. Conflict of interest: W. Funston has nothing to disclose. Conflict of interest: I.A. Forrest reports personal fees for consultancy and meeting attendance from Boehringer Ingelheim, personal fees for lectures and meeting attendance from Roche Ltd, outside the submitted work. Conflict of interest: A.J. Simpson has nothing to disclose. Conflict of interest: M.A. Gibbons has nothing to disclose. Conflict of interest: T.M. Maher has, via his institution, received industry-academic funding from AstraZeneca and GlaxoSmithKline R&D, and has received consultancy or speaker fees from AstraZeneca, Bayer, Blade Therapeutics, Boehringer Ingelheim, Bristol-Myers Squibb, Galapagos, GlaxoSmithKline R&D, Indalo, Novartis, Pliant, Respivant, Roche and Samumed., (Copyright ©ERS 2021.)