Trends in Immunology最新文献

Nociceptors have emerged as master regulators of immune responses in both homeostatic and pathologic settings; however, their seemingly contradictory effects on the functions of different immune cell subsets have been a source of confusion. Nevertheless, work by many groups in recent years has begun to identify patterns of the modalities and consequences of nociceptor-immune system communication. Here, we review recent findings of how nociceptors affect immunity and propose an integrated concept whereby nociceptors are neither inherently pro- nor anti-inflammatory. Rather, we propose that nociceptors have the role of a rheostat that, in a context-dependent manner, favors tissue homeostasis and fine-tunes immunity by preventing excessive histotoxic inflammation, promoting tissue repair, and potentiating anticipatory and adaptive immune responses.

Thromboinflammation is a peculiar and key component of acute COVID-19 pathogenesis, which contributes to long COVID. In a recent study, Ryu et al. demonstrate that the SARS-CoV-2 spike protein interacts with fibrinogen, promoting fibrin polymerization and its inflammatory activity. Targeting the inflammatory fibrin peptide protected mice from spike-dependent fibrin clotting and neuropathology.

Neural cells in our central nervous system (CNS) have long been thought to be mere targets of neuroinflammatory events in neurodegenerative diseases such as multiple sclerosis (MS) or Alzheimer's disease. While glial populations such as microglia and astrocytes emerged as active responders and modifiers of pathological environments, oligodendroglia and neurons have been associated with altered homeostasis and eventual cell death. The advent of single-cell and spatial omics technologies has demonstrated transitions of CNS-resident glia, including oligodendroglia, into disease-associated (DA) states. Anchored in recent findings of their roles in MS, we propose that DA glia constitute key nexus of disease progression, with DA oligodendroglia contributing to the modulation of neuroinflammation in certain neurodegenerative diseases, constituting novel putative pharmacological targets for such pathologies.

The astrocyte, a major glial cell type in the central nervous system (CNS), is widely regarded as a functionally diverse mediator of homeostasis. During development and throughout adulthood, astrocytes have essential roles, such as providing neuron metabolic support, modulating synaptic function, and maintaining the blood-brain barrier (BBB). Recent evidence continues to underscore their functional heterogeneity and importance for CNS maintenance, as well as how these cells ensure optimal CNS and immune responses to disease, acute trauma, and infection. Advances in our understanding of neuroimmune interactions complement our knowledge of astrocyte functional heterogeneity, where astrocytes are now regarded as key effectors and propagators of immune signaling. This shift in perspective highlights the role of astrocytes not merely as support cells, but as active participants in CNS immune responses.

Reciprocal communication between the brain and the immune system is essential for maintaining lifelong brain function. This interaction is mediated, at least in part, by immune cells recruited from both the circulation and niches at the borders of the brain. Here, we describe how immune exhaustion and senescence, even if not primary causative factors, can accelerate neurodegenerative diseases. We emphasize the role of a compromised peripheral immune system in driving neurodegeneration and discuss strategies for harnessing peripheral immunity to effectively treat neurodegenerative diseases, including the underlying mechanisms and opportunities for clinical translation. Specifically, we highlight the potential of boosting the immune system by blocking inhibitory checkpoint molecules to harness reparative immune cells in helping the brain to fight against neurodegeneration.

Circulating immune cells contribute to the pathogenesis of Alzheimer's disease (AD), but their role is poorly understood. Rosenzweig et al. recently identified a subset of interleukin (IL)-17⁺ neutrophils that inhibit neuroprotective microglia in female APOE4 carriers. Blockade of IL-17 signaling or APOE4 deletion in neutrophils restored microglial responses and reduced murine amyloid pathology.

A healthy mammalian central nervous system (CNS) harbors a diverse population of leukocytes including members of the mononuclear phagocyte system (MPS). Exerting their specific functions, CNS tissue-resident macrophages as well as associated monocytes and dendritic cells (DCs) maintain CNS homeostasis. Under neuroinflammatory conditions, leukocytes from the systemic immune compartment invade the CNS. This review focuses on the newly discovered roles of the MPS in autoimmune neuroinflammation elicited by encephalitogenic T cells. We propose that CNS-associated DCs act as gatekeepers and antigen-presenting cells that guide the adaptive immune response while bone marrow (BM)-derived monocytes contribute to immunopathology and tissue damage. By contrast, CNS-resident macrophages primarily support tissue function and promote the repair and maintenance of CNS functions.

During mammalian aging, senescent cells accumulate in the body. Recent evidence suggests that senescent cells potentially contribute to age-related neurodegenerative diseases in the central nervous system (CNS), including tauopathies such as Alzheimer's disease (AD). Senescent cells undergo irreversible cell cycle arrest and release an inflammatory 'senescence-associated secretory profile' (SASP), which can exert devastating effects on surrounding cells. Senescent markers and SASP factors have been detected in multiple brain cells in tauopathies, including microglia, astrocytes, and perhaps even post-mitotic neurons, possibly contributing to the initiation as well as progression of these diseases. Here, we discuss the implications of presenting a senescent phenotype in tauopathies and highlight a potential role for the NOD-like receptor protein 3 (NLRP3) inflammasome as a newfound mechanism implicated in senescence and SASP formation.

Cancers hijack the nervous system for growth and spread. Thus, disrupting neuron-cancer crosstalk holds promise for blocking metastasis. Recently, Padmanaban et al. reported new therapeutic targets and showed that breast cancer cells activate sensory neurons to secrete the neuropeptide substance P (SP), leading to single-strand (ss)RNA release and noncanonical Toll-like receptor (TLR)7 signaling that drives metastasis.