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The majority of lung cancer patients progressing from conventional therapies are refractory to PD‐L1/PD‐1 blockade monotherapy. Here, we show that baseline systemic CD4 immunity is a differential factor for clinical responses. Patients with functional systemic CD4 T cells included all objective responders and could be identified before the start of therapy by having a high proportion of memory CD4 T cells. In these patients, CD4 T cells possessed significant proliferative capacities, low co‐expression of PD‐1/LAG‐3 and were responsive to PD‐1 blockade ex vivo and in vivo . In contrast, patients with dysfunctional systemic CD4 immunity did not respond even though they had lung cancer‐specific T cells. Although proficient in cytokine production, CD4 T cells in these patients proliferated very poorly, strongly co‐upregulated PD‐1/LAG‐3, and were largely refractory to PD‐1 monoblockade. CD8 immunity only recovered in patients with functional CD4 immunity. T‐cell proliferative dysfunctionality could be reverted by PD‐1/LAG‐3 co‐blockade. Patients with functional CD4 immunity and PD‐L1 tumor positivity exhibited response rates of 70%, highlighting the contribution of CD4 immunity for efficacious PD‐L1/PD‐1 blockade therapy. Synopsis Lung cancer patients are often refractory to PD‐L1/PD‐1 blockade therapy. This study shows that patients progressing from conventional therapies that have functional CD4 T cells respond to PD‐L1/PD‐1 blockade immunotherapy, while patients with proliferative dysfunctional CD4 T cells do not respond. Functional systemic CD4 immunity is required for objective clinical responses to PD‐L1/PD‐1 blockade therapy in human lung cancer patients. Systemic memory CD4 T cells identify intrinsic non‐responder from potentially responder patients. 70% of patients with high baseline percentages of memory CD4 T cells and PD‐L1‐positive tumors respond to therapy. Proliferative CD4 dysfunctionality in non‐responder patients can be overcome by PD‐1/LAG‐3 co‐blockade. Graphical Abstract Lung cancer patients are often refractory to PD‐L1/PD‐1 blockade therapy. This study shows that patients progressing from conventional therapies that have functional CD4 T cells respond to PD‐L1/PD‐1 blockade immunotherapy, while patients with proliferative dysfunctional CD4 T cells do not respond.

P2X 7 receptors are ATP‐gated cation channels; their activation in macrophage also leads to rapid opening of a membrane pore permeable to dyes such as ethidium, and to release of the pro‐inflammatory cytokine, interleukin‐1β (IL‐1β). It has not been known what this dye‐uptake path is, or whether it is involved in downstream signalling to IL‐1β release. Here, we identify pannexin‐1, a recently described mammalian protein that functions as a hemichannel when ectopically expressed, as this dye‐uptake pathway and show that signalling through pannexin‐1 is required for processing of caspase‐1 and release of mature IL‐1β induced by P2X 7 receptor activation.

Immunological mechanisms have come into the focus of current translational stroke research, and the modulation of neuroinflammatory pathways has been identified as a promising therapeutic approach to protect the ischemic brain. However, stroke not only induces a local neuroinflammatory response but also has a profound impact on systemic immunity. In this review, we will summarize the consequences of ischemic stroke on systemic immunity at all stages of the disease, from onset to long‐term outcome, and discuss underlying mechanisms of systemic brain‐immune communication. Furthermore, since stroke commonly occurs in patients with multiple comorbidities, we will also overview the current understanding of the potential role of systemic immunity in common stroke‐related comorbidities, such as cardiac dysfunction, atherosclerosis, diabetes, and infections. Finally, we will highlight how targeting systemic immunity after stroke could improve long‐term outcomes and alleviate comorbidities of stroke patients. Graphical Abstract This Review discusses the impact of ischemic stroke on systemic immunity, its interaction with common comorbidities, and the underlying mechanisms of systemic brain‐immune communication.

Neuroinflammation and neurodegeneration often result from the aberrant deposition of aggregated host proteins, including amyloid‐β, α‐synuclein, and prions, that can activate inflammasomes. Inflammasomes function as intracellular sensors of both microbial pathogens and foreign as well as host‐derived danger signals. Upon activation, they induce an innate immune response by secreting the inflammatory cytokines interleukin (IL)‐1β and IL‐18, and additionally by inducing pyroptosis, a lytic cell death mode that releases additional inflammatory mediators. Microglia are the prominent innate immune cells in the brain for inflammasome activation. However, additional CNS‐resident cell types including astrocytes and neurons, as well as infiltrating myeloid cells from the periphery, express and activate inflammasomes. In this review, we will discuss current understanding of the role of inflammasomes in common degenerative diseases of the brain and highlight inflammasome‐targeted strategies that may potentially treat these diseases. Graphical Abstract What is the role of inflammasomes in degenerative diseases like Alzheimer's, Parkinson's, Huntington's, prion diseases, ALS, MS, stroke, TBI and spinal cord injury? Current understandings are here discussed along with potential inflammasome‐targeted strategies to treat these diseases.

Sepsis is a highly lethal and urgent unmet medical need. It is the result of a complex interplay of several pathways, including inflammation, immune activation, hypoxia, and metabolic reprogramming. Specifically, the regulation and the impact of the latter have become better understood in which the highly catabolic status during sepsis and its similarity with starvation responses appear to be essential in the poor prognosis in sepsis. It seems logical that new interventions based on the recognition of new therapeutic targets in the key metabolic pathways should be developed and may have a good chance to penetrate to the bedside. In this review, we concentrate on the pathological changes in metabolism, observed during sepsis, and the presumed underlying mechanisms, with a focus on the level of the organism and the interplay between different organ systems. Graphical Abstract In this review, Van Wingene, Vandewalle and Libert concentrate on the pathological changes in metabolism observed during sepsis, and the presumed underlying mechanisms.

Sepsis has been identified by the World Health Organization (WHO) as a global health priority. There has been a tremendous effort to decipher underlying mechanisms responsible for organ failure and death, and to develop new treatments. Despite saving thousands of animals over the last three decades in multiple preclinical studies, no new effective drug has emerged that has clearly improved patient outcomes. In the present review, we analyze the reasons for this failure, focusing on the inclusion of inappropriate patients and the use of irrelevant animal models. We advocate against repeating the same mistakes and propose changes to the research paradigm. We discuss the long‐term consequences of surviving sepsis and, finally, list some putative approaches—both old and new—that could help save lives and improve survivorship. Graphical Abstract This review recapitulates our knowledge on sepsis and its long‐term consequences, the lack of therapeutic advances in the last decades, and proposes new approaches to improve sepsis survival.

Triggering receptor expressed on myeloid cells 2 (TREM2) is essential for the transition of homeostatic microglia to a disease‐associated microglial state. To enhance TREM2 activity, we sought to selectively increase the full‐length protein on the cell surface via reducing its proteolytic shedding by A Disintegrin And Metalloproteinase (i.e., α‐secretase) 10/17. We screened a panel of monoclonal antibodies against TREM2, with the aim to selectively compete for α‐secretase‐mediated shedding. Monoclonal antibody 4D9, which has a stalk region epitope close to the cleavage site, demonstrated dual mechanisms of action by stabilizing TREM2 on the cell surface and reducing its shedding, and concomitantly activating phospho‐SYK signaling. 4D9 stimulated survival of macrophages and increased microglial uptake of myelin debris and amyloid β‐peptide in vitro . In vivo target engagement was demonstrated in cerebrospinal fluid, where nearly all soluble TREM2 was 4D9‐bound. Moreover, in a mouse model for Alzheimer's disease‐related pathology, 4D9 reduced amyloidogenesis, enhanced microglial TREM2 expression, and reduced a homeostatic marker, suggesting a protective function by driving microglia toward a disease‐associated state. Synopsis This study describes the discovery and characterization of a novel TREM2 antibody, which induces protective microglial functions and provides a basis for the development of human antibodies with a similar mechanistic profile for treatment of Alzheimer's disease. An antibody directed to the stalk region of TREM2 prevents its shedding and increases cell autonomous signaling. Addition of this TREM2 antibody to myeloid cells in vitro stimulates phagocytosis, and improves cell survival. TREM2 antibody treatment increases TREM2 expression on brain microglia, decreases homeostatic markers and reduces amyloid plaque pathology in a mouse model of Alzheimer's disease. Antibody mediated stimulation of TREM2 signaling may be efficacious in Alzheimer's disease as well as other neurodegenerative disorders and obesity‐associated metabolic syndromes. Graphical Abstract This study describes the discovery and characterization of a novel TREM2 antibody, which induces protective microglial functions and provides a basis for the development of human antibodies with a similar mechanistic profile for treatment of Alzheimer's disease.

Cytosolic double‐stranded DNA (dsDNA) is a danger signal that is tightly monitored and sensed by nucleic acid‐sensing pattern recognition receptors. We study the inflammatory cascade on dsDNA recognition and investigate the neuroprotective effect of cyclic GMP‐AMP (cGAMP) synthase (cGAS) antagonist A151 and its mechanisms of neuroprotection in a mouse model of experimental stroke. Here, we found that cerebral ischemia promoted the release of dsDNA into the cytosol, where it initiated inflammatory responses by activating the cGAS. A151 effectively reduced the expression of cGAS, absent in melanoma 2 (AIM2) inflammasome, and pyroptosis‐related molecules, including caspase‐1, gasdermin D, IL‐1β, and IL‐18. Furthermore, mice treated with A151 showed a dampened immune response to stroke, with reduced counts of neutrophils, microglia, and microglial production of IL‐6 and TNF‐α after MCAO. Moreover, A151 administration significantly reduced infarct volume, attenuated neurodeficits, and diminished cell death. Notably, the protective effect of A151 was blocked in a microglia‐specific cGAS knockout mouse. These findings offer unique perspectives on stroke pathogenesis and indicate that inhibition of cGAS could attenuate brain inflammatory burden, representing a potential therapeutic opportunity for stroke. Synopsis Inflammation is involved in the progression of ischemic brain injury. This study focuses on the inflammatory cascade on double‐strand DNA (dsDNA) recognition and highlights the possibility of inhibiting dsDNA‐sensing cyclic GMP‐AMP synthase (cGAS) for treatment of ischemic stroke. The release of dsDNA from necrotic tissue during brain infarction triggers an innate inflammatory cascade. A synthetic oligonucleotide A151 that antagonizes cGAS regulates the microglial immune response and pyroptosis after ischemic stroke. Inhibition of cGAS leads to a decline in neutrophil infiltration into the brain. Suppression of the dsDNA‐sensing cGAS pathway reduces ischemic brain injury via mitigating neuroinflammation. Graphical Abstract Inflammation is involved in the progression of ischemic brain injury. This study focuses on the inflammatory cascade on double‐strand DNA (dsDNA) recognition and highlights the possibility of inhibiting dsDNA‐sensing cyclic GMP‐AMP synthase (cGAS) for treatment of ischemic stroke.

Niacin, as an antidyslipidemic drug, elicits a strong flushing response by release of prostaglandin (PG) D 2 . However, whether niacin is beneficial for inflammatory bowel disease (IBD) remains unclear. Here, we observed niacin administration‐enhanced PGD 2 production in colon tissues in dextran sulfate sodium (DSS)‐challenged mice, and protected mice against DSS or 2,4,6‐trinitrobenzene sulfonic acid (TNBS)‐induced colitis in D prostanoid receptor 1 (DP1)‐dependent manner. Specific ablation of DP1 receptor in vascular endothelial cells, colonic epithelium, and myeloid cells augmented DSS/TNBS‐induced colitis in mice through increasing vascular permeability, promoting apoptosis of epithelial cells, and stimulating pro‐inflammatory cytokine secretion of macrophages, respectively. Niacin treatment improved vascular permeability, reduced apoptotic epithelial cells, promoted epithelial cell update, and suppressed pro‐inflammatory gene expression of macrophages. Moreover, treatment with niacin‐containing retention enema effectively promoted UC clinical remission and mucosal healing in patients with moderately active disease. Therefore, niacin displayed multiple beneficial effects on DSS/TNBS‐induced colitis in mice by activation of PGD 2 /DP1 axis. The potential efficacy of niacin in management of IBD warrants further investigation. Synopsis Niacin, an ancient lipid‐lowering drug that elicits a strong flushing response through release of prostaglandin (PG) D 2 . Niacin improves experimentally induced ulcerative colitis in mice and humans through the activation of PGD 2 /DP1 axis. Niacin increases PGD 2 release in both mice and humans. Niacin confers protection against DSS/TNBS‐induced colitis in mice through DP1‐mediated inhibition of vascular leakage, suppression of colonic epithelium apoptosis, and reduction of pro‐inflammatory cytokine secretion. Retention enema treatment containing niacin effectively promotes clinical remission and mucosal healing in patients with moderately active UC. Graphical Abstract Niacin, an ancient lipid‐lowering drug that elicits a strong flushing response through release of prostaglandin (PG) D 2 . Niacin improves experimentally induced ulcerative colitis in mice and humans through the activation of PGD 2 /DP1 axis.

The dysregulation of NLRP3 inflammasome can cause uncontrolled inflammation and drive the development of a wide variety of human diseases, but the medications targeting NLRP3 inflammasome are not available in clinic. Here, we show that tranilast (TR), an old anti‐allergic clinical drug, is a direct NLRP3 inhibitor. TR inhibits NLRP3 inflammasome activation in macrophages, but has no effects on AIM2 or NLRC4 inflammasome activation. Mechanismly, TR directly binds to the NACHT domain of NLRP3 and suppresses the assembly of NLRP3 inflammasome by blocking NLRP3 oligomerization. In vivo experiments show that TR has remarkable preventive or therapeutic effects on the mouse models of NLRP3 inflammasome‐related human diseases, including gouty arthritis, cryopyrin‐associated autoinflammatory syndromes, and type 2 diabetes. Furthermore, TR is active ex vivo for synovial fluid mononuclear cells from patients with gout. Thus, our study identifies the old drug TR as a direct NLRP3 inhibitor and provides a potentially practical pharmacological approach for treating NLRP3‐driven diseases. Synopsis Tranilast (TR), an anti‐allergic clinical drug, is here reported as a NLRP3 inflammasome inhibitor with beneficial effects for NLRP3‐driven diseases. By direct binding to NLRP3, it inhibits its oligomerization and subsequent inflammasome assembly, caspase‐1 activation and IL‐1β production. TR specifically inhibits NLRP3 inflammasome activation in both human and mouse cells. TR binds to NLRP3 and inhibits its oligomerization and inflammasome complex formation. TR has remarkable preventive or therapeutic effects on the mouse models of NLRP3‐driven diseases. Graphical Abstract Tranilast (TR), an anti‐allergic clinical drug, is here reported as a NLRP3 inflammasome inhibitor with beneficial effects for NLRP3‐driven diseases. By direct binding to NLRP3, it inhibits its oligomerization and subsequent inflammasome assembly, caspase‐1 activation and IL‐1β production.