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Chronic lung allograft dysfunction (CLAD) remains the major barrier to long‐term survival after lung transplantation and improved insight into its underlying immunological mechanisms is critical to better understand the disease and to identify treatment targets. We systematically searched the electronic databases of PubMed and EMBASE for original research publications, published between January 2000 and April 2021, to comprehensively assess current evidence on effector immune cells in lung tissue and bronchoalveolar lavage fluid from lung transplant recipients with CLAD. Literature search revealed 1351 articles, 76 of which met the criteria for inclusion in our analysis. Our results illustrate significant complexity in both innate and adaptive immune cell responses in CLAD, along with presence of numerous immune cell products, including cytokines, chemokines and proteases associated with tissue remodelling. A clear link between neutrophils and eosinophils and CLAD incidence has been seen, in which eosinophils more specifically predisposed to restrictive allograft syndrome. The presence of cytotoxic and T‐helper cells in CLAD pathogenesis is well‐documented, although it is challenging to draw conclusions about their role in tissue processes from predominantly bronchoalveolar lavage data. In restrictive allograft syndrome, a more prominent humoral immune involvement with increased B cells, immunoglobulins and complement deposition is seen. Our evaluation of published studies over the last 20 years summarizes the complex multifactorial immunopathology of CLAD onset and progression. It highlights the phenotype of several key effector immune cells involved in CLAD pathogenesis, as well as the paucity of single cell resolution spatial studies in lung tissue from patients with CLAD. [ABSTRACT FROM AUTHOR]

Summary: Chemokines (chemotactic cytokines) and their receptors are critical to recruitment and positioning of cells during development and the immune response. The chemokine system has long been described as redundant for a number of reasons, where multiple chemokine ligands can bind to multiple receptors and vice versa. This apparent redundancy has been thought to be a major reason for the failure of drugs targeting chemokines during inflammatory disease. We are now beginning to understand that chemokine biology is in fact based around a high degree of specificity, where each chemokine and receptor plays a particular role in the immune response. This specificity hypothesis is supported by a number of recent studies designed to address this problem. This review will detail these studies and the mechanisms that produce this specificity of function with an emphasis on the emerging role of chemokine–glycosaminoglycan interactions. [ABSTRACT FROM AUTHOR]

Summary: Macrophage activation is characterized by pronounced metabolic adaptation. Classically activated macrophages show decreased rates of mitochondrial fatty acid oxidation and oxidative phosphorylation and acquire a glycolytic state together with their pro‐inflammatory phenotype. In contrast, alternatively activated macrophages require oxidative phosphorylation and mitochondrial fatty acid oxidation for their anti‐inflammatory function. Although it is evident that mitochondrial metabolism is regulated during macrophage polarization and essential for macrophage function, little is known on the regulation and role of peroxisomal β‐oxidation during macrophage activation. In this study, we show that peroxisomal β‐oxidation is strongly decreased in classically activated bone‐marrow‐derived macrophages (BMDM) and mildly induced in alternatively activated BMDM. To examine the role of peroxisomal β‐oxidation in macrophages, we used Mfp2−/− BMDM lacking the key enzyme of this pathway. Impairment of peroxisomal β‐oxidation in Mfp2−/− BMDM did not cause lipid accumulation but rather an altered distribution of lipid species with very‐long‐chain fatty acids accumulating in the triglyceride and phospholipid fraction. These lipid alterations in Mfp2−/− macrophages led to decreased inflammatory activation of Mfp2−/− BMDM and peritoneal macrophages evidenced by impaired production of several inflammatory cytokines and chemokines, but did not affect anti‐inflammatory polarization. The disturbed inflammatory responses of Mfp2−/− macrophages did not affect immune cell infiltration, as mice with selective elimination of MFP2 from myeloid cells showed normal monocyte and neutrophil influx upon challenge with zymosan. Together, these data demonstrate that peroxisomal β‐oxidation is involved in fine‐tuning the phenotype of macrophages, probably by influencing the dynamic lipid profile during macrophage polarization. [ABSTRACT FROM AUTHOR]

Dengue virus ( DENV) infection causes dengue fever, dengue haemorrhagic fever, or dengue shock syndrome. Mast cells have been speculated to play a role in DENV disease although their precise roles are unclear. In this study, we used mast cell-deficient KitW-sh/W-sh mice to investigate the involvement of mast cells after intradermal DENV infection. An approximately two- to three-fold higher level of DENV NS3 antigen was detected at the skin inoculation site in DENV-infected KitW-sh/W-sh mice than in DENV-infected wild-type ( WT) mice (using a dose of 1 × 109 plaque-forming units/mouse). Moreover, as an indicator of heightened pathogenesis, a more prolonged bleeding time was observed in DENV-infected KitW-sh/W-sh mice than in WT mice. Monocytes/macrophages are considered to be important targets for DENV infection, so we investigated the susceptibility and chemokine response of DENV-infected peritoneal macrophages from KitW-sh/W-sh and WT mice both ex vivo and in vivo. There was a tendency for higher DENV infection and higher secretion of CCL2 ( MCP-1) from peritoneal macrophages isolated from KitW-sh/W-sh mice than those from WT mice. In vivo studies using intradermal inoculation of DENV showed about twofold higher levels of infiltrating macrophages and CCL2 ( MCP-1) at the inoculation site in both mock control and DENV-inoculated KitW-sh/W-sh mice than in corresponding WT mice. In summary, compared with WT mice, KitW-sh/W-sh mice show enhanced DENV infection and macrophage infiltration at the skin inoculation site as well as increased DENV-associated bleeding time. The results indicate an intriguing interplay between mast cells and tissue macrophages to restrict DENV replication in the skin. [ABSTRACT FROM AUTHOR]

The frequency of CD4+ Foxp3+ regulatory T (Treg) cells is often significantly increased in the blood of tumour-bearing mice and people with cancer. Moreover, Treg cell frequencies are often higher in tumours compared with blood and lymphoid organs. We wished to determine whether certain chemokines expressed within the tumour mass selectively recruit Treg cells, thereby contributing to their enrichment within the tumour-infiltrating lymphocyte pool. To achieve this goal, the chemokine profile of carcinogen-induced fibrosarcomas was determined, and the chemokine receptor expression profiles of both CD4+ Foxp3− and CD4+ Foxp3+ T cells were compared. These analyses revealed that the tumours are characterized by expression of inflammatory chemokines ( CCL2, CCL5, CCL7, CCL8, CCL12, CXCL9, CXCL10 and CX3 CL1), reflected by an enrichment of activated Foxp3− and Foxp3+ T cells expressing T helper type 1-associated chemokine receptors. Notably, we found that CXCR3+ T cells were significantly enriched in the tumours although curiously we found no evidence that CXCR3 was required for their recruitment. Instead, CXCR3 marks a population of activated Foxp3− and Foxp3+ T cells, which use multiple and overlapping ligand receptor pairs to guide their migration to tumours. Collectively, these data indicate that enrichment of Foxp3+ cells in tumours characterized by expression of inflammatory chemokines, does not occur via a distinct chemokine axis, thus selective chemokine blockade is unlikely to represent a meaningful therapeutic strategy for preventing Treg cell accumulation in tumours. [ABSTRACT FROM AUTHOR]

Previous studies demonstrated that the CXCL12 peptide analogue CTCE- 0214 (CTCE) has beneficial effects in experimental sepsis induced by caecal ligation and puncture (CLP). We examined the hypothesis that CTCE recruits neutrophils (polymorphonuclear leucocytes; PMN) to the site of infection, enhances PMN function and improves survival of mice in CLPinduced sepsis with antibiotic treatment. Mice with sepsis (n = 15) were administered imipenem (25 mg/kg) and CTCE (10 mg/kg) subcutaneously versus vehicle control at designated intervals post-CLP. CTCE treatment increased PMN recruitment in CLP-induced sepsis, as evidenced by increased PMN in blood, by 2.4 ± 0.6 fold at 18 hr, 2.9 ± 0.6 fold at 24 hr, and in peritoneal fluid by 2.0 ± 0.2 fold at 24 hr versus vehicle control. CTCE treatment reduced bacterial invasion in blood [colonyforming units (CFU) decreased 77 ± 11%], peritoneal fluid (CFU decreased 78 ± 9%) and lung (CFU decreased 79 ± 8% versus CLP vehicle). The improved PMN recruitment and bacterial clearance correlated with reduced mortality with CTCE treatment (20% versus 67% vehicle controls). In vitro studies support the notion that CTCE augments PMN function by enhancing phagocytic activity (1.25 ± 0.02 fold), increasing intracellular production of reactive oxygen species (32 ± 4%) and improving bacterial killing (CFU decreased 27 ± 3%). These composite findings support the hypothesis that specific CXCL12 analogues with ancillary antibiotic treatment are beneficial in experimental sepsis, in part, by augmenting PMN recruitment and function. [ABSTRACT FROM AUTHOR]

Oxidative stress is a major and recurring cause of damage during inflammation, especially following organ transplantation. Initial ischaemia-reperfusion injury causes the production of many reactive oxygen and nitrogen species, and subsequent recruitment and activation of inflammatory cells can lead to further oxidative stress. This stress is well known to cause damage at the cellular level, for example by induction of senescence leading to the production of a characteristic senescence-associated secretory phenotype. Chemokines are an important component of the senescence-associated secretory phenotype, recruiting further leucocytes and reinforcing the stress and senescence responses. As well as inducing the production of proteins, including chemokines, oxidative stress can alter proteins themselves, both directly and by induction of enzymes capable of modification. These alterations can lead to important modifications to their biological activity and also alter detection by some antibodies, potentially limiting the biological relevance of some immunochemical and proteomic biomarkers. Peroxynitrite, a reactive nitrogen species generated during inflammation and ischaemia, can cause such modifications by nitrating chemokines. Matrix metalloproteinases, released by many stressed cells, can cleave chemokines, altering function, while peptidylarginine deiminases can inactivate certain chemokines by citrullination. This review discusses the relationship between inflammation and post-translational modification, focusing on the functional modulation of transplant-relevant pro-inflammatory chemokines. [ABSTRACT FROM AUTHOR]