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Klebsiella pneumoniae , particularly hypervirulent strains (hv Kp ), poses a critical public health threat due to its capacity to cause severe, rapidly progressing infections such as pneumonia and sepsis, often leading to acute lung injury (ALI) and high mortality. Despite the recognized role of excessive inflammation and cytokine storms in hv Kp pathogenesis, the precise mechanisms linking immune hyperactivation to fatal tissue damage remain poorly defined. This study reveals that hv Kp infection triggers a coordinated form of inflammatory cell death, PANoptosis, in AMs, the frontline immune defenders in the lungs. We identify the transcription factor STAT1 as a central regulator of this process, driven by a synergistic cytokine milieu, especially involving IFN-γ. Our findings establish a direct mechanistic pathway from hv Kp -induced cytokine release to STAT1-mediated PANoptosis, macrophage depletion, and subsequent lung failure. This work not only advances the understanding of hv Kp virulence but also highlights host signaling pathways and specific cytokines as potential therapeutic targets to modulate immunopathology and improve outcomes in severe Klebsiella infections.

Anti-cytokine autoantibodies represent an expanding field in immunology, and their study has revealed crucial insights into immune cell dysfunction. These autoantibodies are now classified by the International Union of Immunological Societies (IUIS) as phenocopies of primary immunological deficiencies within the broader category of inborn immunity defects. Indeed, the critical importance of these autoantibodies became starkly apparent during the COVID-19 pandemic when patients with type I interferon autoantibodies showed significantly higher rates of severe illness. This review examines how neutralizing autoantibodies, exemplified by those targeting granulocyte monocyte stimulating factor, can compromise immune function in otherwise immunocompetent individuals, making them more susceptible to specific fungal and bacterial infections. This understanding highlights the crucial role of anti-cytokine antibodies in infection susceptibility and immune system regulation.

Adenosine receptor A2AR plays a pivotal role in dampening pro-inflammatory cytokine levels in Leishmania donovani-infected macrophages, thus promoting infection. However, the specific regulatory pathway remains unidentified. In this study, we showed that blocking A2AR signaling reduces the expression of heme oxygenase-1 (HO-1), an enzyme earlier implicated in reducing pro-inflammatory cytokine levels. A2AR, being a G-protein-coupled receptor (GPCR), increased intracellular cAMP, thereby activating protein kinase A (PKA) activity. Inhibition of the A2AR/PKA pathway impacted two major transcription factors of HO-1, cAMP response element-binding protein (CREB) and nuclear factor erythroid 2-related factor 2 (NRF2). PKA directly activated CREB through phosphorylation, and the ChIP assay further validated the involvement of PKA in p-CREB-mediated HO-1 transcription. On the other hand, PKA-mediated glycogen synthase kinase-3 beta (GSK-3β) phosphorylation at the Ser-9 position rendered it inactive and removed its inhibitory effect on NRF2, thus allowing its nuclear translocation during infection. Macrophages transfected with constitutively active nonphosphorylated GSK-3β showed reduced nuclear localization of NRF2 and decreased parasite survival. Administering the A2AR inhibitor in infected mice decreased HO-1 levels, liver and spleen parasite burden, and increased pro-inflammatory cytokine levels. Our findings revealed Leishmania exploits adenosine-A2AR signaling to activate PKA-mediated CREB- and NRF2-dependent HO-1 upregulation, reducing pro-inflammatory cytokine levels and favoring pathogenesis.IMPORTANCEVisceral leishmaniasis, caused by the protozoan parasite Leishmania donovani, is a major health concern affecting over a million people worldwide. An increase in host ATP production and its efflux benefits the survival of Leishmania parasites and prolongs the infection. Effluxed ATP is converted to adenosine, which activates adenosine-A2AR signaling to provide an immunosuppressive milieu, necessary for infection propagation. This study identified cAMP/PKA as the essential components of A2AR signaling, which further differentially activate two transcription factors to induce the antioxidant enzyme HO-1, responsible for creating the anti-inflammatory environment. Our findings highlight A2AR as a promising drug target against visceral leishmaniasis and other inflammation-related diseases, offering us the opportunity to alleviate inflammatory responses, thereby broadening the impact on disease management and therapy.

CRC remains a leading cause of cancer death worldwide, and new therapeutic approaches are urgently needed. Our study reveals that NaB, a natural gut‐derived metabolite, can reshape the tumor immune environment by limiting pro‐tumor M2 macrophages and reducing PD-L1 + macrophage infiltration. By combining single‐cell transcriptomics with mouse models, we pinpoint how butyrate acts through the HDAC/TLR4/MyD88 pathway and demonstrate its synergy with PD-L1 blockade. These findings highlight butyrate’s potential as an accessible, low-toxicity agent to boost existing immunotherapies and offer a clear rationale for clinical trials exploring butyrate–immune checkpoint inhibitor combinations in CRC.

Clinical trials using adult stem cells to regenerate damaged heart tissue continue to this day 1 , 2 , despite ongoing questions of efficacy and a lack of mechanistic understanding of the underlying biological effect 3 . The rationale for these cell therapy trials is derived from animal studies that show a modest but reproducible improvement in cardiac function in models of cardiac ischaemic injury 4 , 5 . Here we examine the mechanistic basis for cell therapy in mice after ischaemia–reperfusion injury, and find that—although heart function is enhanced—it is not associated with the production of new cardiomyocytes. Cell therapy improved heart function through an acute sterile immune response characterized by the temporal and regional induction of CCR2 + and CX3CR1 + macrophages. Intracardiac injection of two distinct types of adult stem cells, cells killed by freezing and thawing or a chemical inducer of the innate immune response all induced a similar regional accumulation of CCR2 + and CX3CR1 + macrophages, and provided functional rejuvenation to the heart after ischaemia–reperfusion injury. This selective macrophage response altered the activity of cardiac fibroblasts, reduced the extracellular matrix content in the border zone and enhanced the mechanical properties of the injured area. The functional benefit of cardiac cell therapy is thus due to an acute inflammatory-based wound-healing response that rejuvenates the infarcted area of the heart. Cardiac stem cell therapy in mouse models of ischaemia–reperfusion injury demonstrates that improvement in heart function is linked to an immune response characterized by the induction of CCR2 + and CX3CR1 + macrophages.

Recognition and clearance of a bacterial infection are fundamental properties of innate immunity. Here, we describe an effector B cell population that protects against microbial sepsis. Innate response activator (IRA) B cells are phenotypically and functionally distinct, develop and diverge from Bla B cells, depend on pattern-recognition receptors, and produce granulocyte-macrophage colony-stimulating factor. Specific deletion of IRA B cell activity impairs bacterial clearance, elicits a cytokine storm, and precipitates septic shock. These observations enrich our understanding of innate immunity, position IRA B cells as gatekeepers of bacterial infection, and identify new treatment avenues for infectious diseases.

Acute kidney injury (AKI) is defined by a rapid decline in renal function. Regardless of the initial cause of injury, the influx of immune cells is a common theme during AKI. While an inflammatory response is critical for the initial control of injury, a prolonged response can negatively affect tissue repair. In this review, we focus on the role of macrophages, from early inflammation to resolution, during AKI. These cells serve as the innate defense system by phagocytosing cellular debris and pathogenic molecules and bridge communication with the adaptive immune system by acting as antigen-presenting cells and secreting cytokines. While many immune cells function to initiate inflammation, macrophages play a complex role throughout AKI. This complexity is driven by their functional plasticity: the ability to polarize from a “pro-inflammatory” phenotype to a “pro-reparative” phenotype. Importantly, experimental and translational studies indicate that macrophage polarization opens the possibility to generate novel therapeutics to promote repair during AKI. A thorough understanding of the biological roles these phagocytes play during both injury and repair is necessary to understand the limitations while furthering the therapeutic application.

Lung macrophages (LMs) are essential immune effector cells that are pivotal in both innate and adaptive immune responses to inhaled foreign matter. They either reside within the airways and lung tissues (from early life) or are derived from blood monocytes. Similar to macrophages in other organs and tissues, LMs have natural plasticity and can change phenotype and function depending largely on the microenvironment they reside in. Phenotype changes in lung tissue macrophages have been implicated in chronic inflammatory responses and disease progression of various chronic lung diseases, including Chronic Obstructive Pulmonary Disease (COPD). LMs have a wide variety of functional properties that include phagocytosis (inorganic particulate matter and organic particles, such as viruses/bacteria/fungi), the processing of phagocytosed material, and the production of signaling mediators. Functioning as janitors of the airways, they also play a key role in removing dead and dying cells, as well as cell debris (efferocytic functions). We herein review changes in LM phenotypes during chronic lung disease, focusing on COPD, as well as changes in their functional properties as a result of such shifts. Targeting molecular pathways involved in LM phenotypic shifts could potentially allow for future targeted therapeutic interventions in several diseases, such as COPD.

Monocytes (Mo) and macrophages (Mϕ) are key components of the innate immune system and are involved in regulation of the initiation, development, and resolution of many inflammatory disorders. In addition, these cells also play important immunoregulatory and tissue-repairing roles to decrease immune reactions and promote tissue regeneration. Several lines of evidence have suggested a causal link between the presence or activation of these cells and the development of autoimmune diseases. In addition, Mo or Mϕ infiltration in diseased tissues is a hallmark of several autoimmune diseases. However, the detailed contributions of these cells, whether they actually initiate disease or perpetuate disease progression, and whether their phenotype and functional alteration are merely epiphenomena are still unclear in many autoimmune diseases. Additionally, little is known about their heterogeneous populations in different autoimmune diseases. Elucidating the relevance of Mo and Mϕ in autoimmune diseases and the associated mechanisms could lead to the identification of more effective therapeutic strategies in the future.

The cellular immune response to tissue damage and infection requires the recruitment of blood leukocytes. This process is mediated through a classical multistep mechanism, which involves transient rolling on the endothelium and recognition of inflammation followed by extravasation. We have shown, by direct examination of blood monocyte functions in vivo, that a subset of monocytes patrols healthy tissues through long-range crawling on the resting endothelium. This patrolling behavior depended on the integrin LFA-1 and the chemokine receptor CX₃CR1 and was required for rapid tissue invasion at the site of an infection by this \"resident\" monocyte population, which initiated an early immune response and differentiated into macrophages.