Commensals find their niche
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Conserved immunomodulation and variation in host association by Xanthomonadales commensals in Arabidopsis root microbiota
Suppression of chronic Arabidopsis immune responses is a widespread but typically strain-specific trait across the major bacterial lineages of the plant microbiota. We show by phylogenetic analysis and in planta associations with representative strains that immunomodulation is a highly conserved, ancestral trait across Xanthomonadales, and preceded specialization of some of these bacteria as host-adapted pathogens. Rhodanobacter R179 activates immune responses, yet root transcriptomics suggest this commensal evades host immune perception upon prolonged association. R179 camouflage likely results from combined activities of two transporter complexes (dssAB) and the selective elimination of immunogenic peptides derived from all partners. The ability of R179 to mask itself and other commensals from the plant immune system is consistent with a convergence of distinct root transcriptomes triggered by immunosuppressive or non-suppressive synthetic microbiota upon R179 co-inoculation. Immunomodulation through dssAB provided R179 with a competitive advantage in synthetic communities in the root compartment. We propose that extensive immunomodulation by Xanthomonadales is related to their adaptation to terrestrial habitats and might have contributed to variation in strain-specific root association, which together accounts for their prominent role in plant microbiota establishment.
Microglial mechanisms drive amyloid-β clearance in immunized patients with Alzheimer’s disease
Alzheimer’s disease (AD) therapies utilizing amyloid-β (Aβ) immunization have shown potential in clinical trials. Yet, the mechanisms driving Aβ clearance in the immunized AD brain remain unclear. Here, we use spatial transcriptomics to explore the effects of both active and passive Aβ immunization in the AD brain. We compare actively immunized patients with AD with nonimmunized patients with AD and neurologically healthy controls, identifying distinct microglial states associated with Aβ clearance. Using high-resolution spatial transcriptomics alongside single-cell RNA sequencing, we delve deeper into the transcriptional pathways involved in Aβ removal after lecanemab treatment. We uncover spatially distinct microglial responses that vary by brain region. Our analysis reveals upregulation of the triggering receptor expressed on myeloid cells 2 (TREM2) and apolipoprotein E (APOE) in microglia across immunization approaches, which correlate positively with antibody responses and Aβ removal. Furthermore, we show that complement signaling in brain myeloid cells contributes to Aβ clearance after immunization. These findings provide new insights into the transcriptional mechanisms orchestrating Aβ removal and shed light on the role of microglia in immune-mediated Aβ clearance. Importantly, our work uncovers potential molecular targets that could enhance Aβ-targeted immunotherapies, offering new avenues for developing more effective therapeutic strategies to combat AD.
Targeting of TAMs: can we be more clever than cancer cells?
With increasing incidence and geography, cancer is one of the leading causes of death, reduced quality of life and disability worldwide. Principal progress in the development of new anticancer therapies, in improving the efficiency of immunotherapeutic tools, and in the personification of conventional therapies needs to consider cancer-specific and patient-specific programming of innate immunity. Intratumoral TAMs and their precursors, resident macrophages and monocytes, are principal regulators of tumor progression and therapy resistance. Our review summarizes the accumulated evidence for the subpopulations of TAMs and their increasing number of biomarkers, indicating their predictive value for the clinical parameters of carcinogenesis and therapy resistance, with a focus on solid cancers of non-infectious etiology. We present the state-of-the-art knowledge about the tumor-supporting functions of TAMs at all stages of tumor progression and highlight biomarkers, recently identified by single-cell and spatial analytical methods, that discriminate between tumor-promoting and tumor-inhibiting TAMs, where both subtypes express a combination of prototype M1 and M2 genes. Our review focuses on novel mechanisms involved in the crosstalk among epigenetic, signaling, transcriptional and metabolic pathways in TAMs. Particular attention has been given to the recently identified link between cancer cell metabolism and the epigenetic programming of TAMs by histone lactylation, which can be responsible for the unlimited protumoral programming of TAMs. Finally, we explain how TAMs interfere with currently used anticancer therapeutics and summarize the most advanced data from clinical trials, which we divide into four categories: inhibition of TAM survival and differentiation, inhibition of monocyte/TAM recruitment into tumors, functional reprogramming of TAMs, and genetic enhancement of macrophages.
Neutrophils in cancer: from biology to therapy
The view of neutrophils has shifted from simple phagocytic cells, whose main function is to kill pathogens, to very complex cells that are also involved in immune regulation and tissue repair. These cells are essential for maintaining and regaining tissue homeostasis. Neutrophils can be viewed as double-edged swords in a range of situations. The potent killing machinery necessary for immune responses to pathogens can easily lead to collateral damage to host tissues when inappropriately controlled. Furthermore, some subtypes of neutrophils are potent pathogen killers, whereas others are immunosuppressive or can aid in tissue healing. Finally, in tumor immunology, many examples of both protumorigenic and antitumorigenic properties of neutrophils have been described. This has important consequences for cancer therapy, as targeting neutrophils can lead to either suppressed or stimulated antitumor responses. This review will discuss the current knowledge regarding the pro- and antitumorigenic roles of neutrophils, leading to the concept of a confused state of neutrophil-driven pro-/antitumor responses.
Type 2 immunity in allergic diseases
Significant advancements have been made in understanding the cellular and molecular mechanisms of type 2 immunity in allergic diseases such as asthma, allergic rhinitis, chronic rhinosinusitis, eosinophilic esophagitis (EoE), food and drug allergies, and atopic dermatitis (AD). Type 2 immunity has evolved to protect against parasitic diseases and toxins, plays a role in the expulsion of parasites and larvae from inner tissues to the lumen and outside the body, maintains microbe-rich skin and mucosal epithelial barriers and counterbalances the type 1 immune response and its destructive effects. During the development of a type 2 immune response, an innate immune response initiates starting from epithelial cells and innate lymphoid cells (ILCs), including dendritic cells and macrophages, and translates to adaptive T and B-cell immunity, particularly IgE antibody production. Eosinophils, mast cells and basophils have effects on effector functions. Cytokines from ILC2s and CD4+ helper type 2 (Th2) cells, CD8 + T cells, and NK-T cells, along with myeloid cells, including IL-4, IL-5, IL-9, and IL-13, initiate and sustain allergic inflammation via T cell cells, eosinophils, and ILC2s; promote IgE class switching; and open the epithelial barrier. Epithelial cell activation, alarmin release and barrier dysfunction are key in the development of not only allergic diseases but also many other systemic diseases. Recent biologics targeting the pathways and effector functions of IL4/IL13, IL-5, and IgE have shown promising results for almost all ages, although some patients with severe allergic diseases do not respond to these therapies, highlighting the unmet need for a more detailed and personalized approach.
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