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Over the past two decades, significant progress in understanding of the pathogenesis of type 2 chronic inflammatory diseases has enabled the identification of compounds for more than 20 novel targets, which are approved or at various stages of development, finally facilitating a more targeted approach for the treatment of these disorders. Most of these newly identified pathogenic drivers of type 2 inflammation and their corresponding treatments are related to mast cells, eosinophils, T cells, B cells, epithelial cells and sensory nerves. Epithelial barrier defects and dysbiotic microbiomes represent exciting future drug targets for chronic type 2 inflammatory conditions. Here, we review common targets, current treatments and emerging therapies for the treatment of five major type 2 chronic inflammatory diseases — atopic dermatitis, chronic prurigo, chronic urticaria, asthma and chronic rhinosinusitis with nasal polyps — with a high need for targeted therapies. Unmet needs and future directions in the field are discussed.Increased understanding of the molecular mechanisms underlying type 2 chronic inflammatory diseases has facilitated the development of more targeted therapies for these conditions. Focusing on five major type 2 diseases, this Review provides an overview of the pathogenic drivers of type 2 inflammation, assesses agents that target them and considers emerging novel therapies and unmet needs.

The heterogeneous cellular microenvironment of human airway chronic inflammatory diseases, including chronic rhinosinusitis (CRS) and asthma, is still poorly understood. Here, we performed single-cell RNA sequencing (scRNA-seq) on the nasal mucosa of healthy individuals and patients with three subtypes of CRS and identified disease-specific cell subsets and molecules that specifically contribute to the pathogenesis of CRS subtypes. As such, ALOX15+ macrophages contributed to the type 2 immunity-driven pathogenesis of one subtype of CRS, eosinophilic CRS with nasal polyps (eCRSwNP), by secreting chemokines that recruited eosinophils, monocytes and T helper 2 (TH2) cells. An inhibitor of ALOX15 reduced the release of proinflammatory chemokines in human macrophages and inhibited the overactivation of type 2 immunity in a mouse model of eosinophilic rhinosinusitis. Our findings advance the understanding of the heterogeneous immune microenvironment and the pathogenesis of CRS subtypes and identify potential therapeutic approaches for the treatment of CRS and potentially other type 2 immunity-mediated diseases.Zhang and colleagues use single-cell RNA sequencing on the nasal mucosa to identify cell subsets and molecules that specifically contribute to the pathogenesis of chronic rhinosinusitis subtypes.

Inflammation of non-barrier immunologically quiescent tissues is associated with a massive influx of blood-borne innate and adaptive immune cells. Cues from the latter are likely to alter and expand activated states of the resident cells. However, local communications between immigrant and resident cell types in human inflammatory disease remain poorly understood. Here, we explored drivers of fibroblast-like synoviocyte (FLS) heterogeneity in inflamed joints of patients with rheumatoid arthritis using paired single-cell RNA and ATAC sequencing, multiplexed imaging and spatial transcriptomics along with in vitro modeling of cell-extrinsic factor signaling. These analyses suggest that local exposures to myeloid and T cell-derived cytokines, TNF, IFN-γ, IL-1β or lack thereof, drive four distinct FLS states some of which closely resemble fibroblast states in other disease-affected tissues including skin and colon. Our results highlight a role for concurrent, spatially distributed cytokine signaling within the inflamed synovium. Smith et al. present a resource detailing drivers of transcriptional heterogeneity of synovial fibroblasts cell states in the inflamed joints of human patients with rheumatoid arthritis.

Netea and colleagues provide a general guide to the cellular and humoral contributors to inflammation as well as the pathways that characterize inflammation in specific organs and tissues. Biologists, physicians and immunologists have contributed to the understanding of the cellular participants and biological pathways involved in inflammation. Here, we provide a general guide to the cellular and humoral contributors to inflammation as well as to the pathways that characterize inflammation in specific organs and tissues.

Atopic dermatitis (AD) is a common chronic inflammatory skin disease with a complex pathophysiology that underlies a wide spectrum of clinical phenotypes. AD remains challenging to treat owing to the limited response to available therapies. However, recent advances in understanding of disease mechanisms have led to the discovery of novel potential therapeutic targets and drug candidates. In addition to regulatory approval for the IL-4Ra inhibitor dupilumab, the anti-IL-13 inhibitor tralokinumab and the JAK1/2 inhibitor baricitinib in Europe, there are now more than 70 new compounds in development. This Review assesses the various strategies and novel agents currently being investigated for AD and highlights the potential for a precision medicine approach to enable prevention and more effective long-term control of this complex disease.Recent advances in understanding of the complex phenotype and mechanisms underlying atopic dermatitis (AD) have revealed multiple new potential targets for pharmacological intervention. Here, Bieber reviews therapeutic strategies and assesses the expanding pipeline for the therapy of AD, highlighting the potential for a precision medicine approach to the management of this complex disorder.

The identification of lymphocyte subsets with non-overlapping effector functions has been pivotal to the development of targeted therapies in immune-mediated inflammatory diseases (IMIDs) 1 , 2 . However, it remains unclear whether fibroblast subclasses with non-overlapping functions also exist and are responsible for the wide variety of tissue-driven processes observed in IMIDs, such as inflammation and damage 3 , 4 – 5 . Here we identify and describe the biology of distinct subsets of fibroblasts responsible for mediating either inflammation or tissue damage in arthritis. We show that deletion of fibroblast activation protein-α (FAPα) + fibroblasts suppressed both inflammation and bone erosions in mouse models of resolving and persistent arthritis. Single-cell transcriptional analysis identified two distinct fibroblast subsets within the FAPα + population: FAPα + THY1 + immune effector fibroblasts located in the synovial sub-lining, and FAPα + THY1 − destructive fibroblasts restricted to the synovial lining layer. When adoptively transferred into the joint, FAPα + THY1 − fibroblasts selectively mediate bone and cartilage damage with little effect on inflammation, whereas transfer of FAPα + THY1 + fibroblasts resulted in a more severe and persistent inflammatory arthritis, with minimal effect on bone and cartilage. Our findings describing anatomically discrete, functionally distinct fibroblast subsets with non-overlapping functions have important implications for cell-based therapies aimed at modulating inflammation and tissue damage. Distinct subsets of fibroblasts, which differ in their expression of thymus cell antigen 1 (THY1), are responsible for inflammation and tissue damage in mouse models of arthritis.

Obesity is a state of low-grade chronic inflammation that causes multiple metabolic diseases. During obesity, signalling via cytokines of the TNF family mediate cell death and inflammation within the adipose tissue, eventually resulting in lipid spill-over, glucotoxicity and insulin resistance. These events ultimately lead to ectopic lipid deposition, glucose intolerance and other metabolic complications with life-threatening consequences. Here we review the literature on how inflammatory responses affect metabolic processes such as energy homeostasis and insulin signalling. This review mainly focuses on the role of cell death in the adipose tissue as a key player in metabolic inflammation.

Naive T cells undergo radical changes during the transition from dormant to hyperactive states upon activation, which necessitates de novo protein production via transcription and translation. However, the mechanism whereby T cells globally promote translation remains largely unknown. Here, we show that on exit from quiescence, T cells upregulate transfer RNA (tRNA) m1A58 ‘writer’ proteins TRMT61A and TRMT6, which confer m1A58 RNA modification on a specific subset of early expressed tRNAs. These m1A-modified early tRNAs enhance translation efficiency, enabling rapid and necessary synthesis of MYC and of a specific group of key functional proteins. The MYC protein then guides the exit of naive T cells from a quiescent state into a proliferative state and promotes rapid T cell expansion after activation. Conditional deletion of the Trmt61a gene in mouse CD4+ T cells causes MYC protein deficiency and cell cycle arrest, disrupts T cell expansion upon cognate antigen stimulation and alleviates colitis in a mouse adoptive transfer colitis model. Our study elucidates for the first time, to our knowledge, the in vivo physiological roles of tRNA-m1A58 modification in T cell-mediated pathogenesis and reveals a new mechanism of tRNA-m1A58-controlled T cell homeostasis and signal-dependent translational control of specific key proteins.Naive T cells are quiescent but undergo dynamic changes upon antigenic activation. Li and colleagues show that upregulation of tRNA methyltransferase complex TRMT61A–TRMT6 and N1-methyladenosine modification of tRNAs contribute to accelerated mRNA translation efficiency, in particular that of MYC protein, and are required for rapid T cell proliferation.

Fibroblasts are present throughout the body and function to maintain tissue homeostasis. Recent studies have identified diverse fibroblast subsets in healthy and injured tissues 1 , 2 , but the origins and functional roles of injury-induced fibroblast lineages remain unclear. Here we show that lung-specialized alveolar fibroblasts take on multiple molecular states with distinct roles in facilitating responses to fibrotic lung injury. We generate a genetic tool that uniquely targets alveolar fibroblasts to demonstrate their role in providing niches for alveolar stem cells in homeostasis and show that loss of this niche leads to exaggerated responses to acute lung injury. Lineage tracing identifies alveolar fibroblasts as the dominant origin for multiple emergent fibroblast subsets sequentially driven by inflammatory and pro-fibrotic signals after injury. We identify similar, but not completely identical, fibroblast lineages in human pulmonary fibrosis. TGFβ negatively regulates an inflammatory fibroblast subset that emerges early after injury and stimulates the differentiation into fibrotic fibroblasts to elicit intra-alveolar fibrosis. Blocking the induction of fibrotic fibroblasts in the alveolar fibroblast lineage abrogates fibrosis but exacerbates lung inflammation. These results demonstrate the multifaceted roles of the alveolar fibroblast lineage in maintaining normal alveolar homeostasis and orchestrating sequential responses to lung injury. In mouse and human, lung-specialized alveolar fibroblasts adopt multiple molecular states that are induced by pro-inflammatory and fibrotic signals and have diverse protective roles against lung injury.

Key Points Inflammation is a beneficial process, designed to contain and eradicate threats to the host organism. Dysregulation of the magnitude or duration of inflammation contributes to multiple pathologies. Traditionally, drugs have been designed to reduce inflammation. Some such approaches — for example, non-steroidal anti-inflammatory drugs or pro-inflammatory cytokine ablation — achieve this by targeting factors that drive inflammation; others — for example, glucocorticoids — are directly anti-inflammatory. Active, specialized pathways bring about the resolution of inflammation. These involve discrete mediators and distinct cell phenotypes that act in a non-phlogistic manner to promote the clearance of inflammatory cells and a return to local tissue homeostasis. Recent advances in our understanding of the central processes in the resolution of inflammation — including pro-inflammatory mediator catabolism, dampening of downstream signalling, apoptosis and efferocytosis of inflammatory cells and their regulation — permit targeted pharmacological interventions to promote inflammatory resolution. The development of drugs that promote or mimic the mode of action of endogenous pro-resolution pathways may afford a novel complementary, or potentially superior, strategy to traditional options — thus regulating inflammation and restoring function, not merely suppressing inflammation. Recent discoveries suggest that the innate immune response, and in particular its resolution, may modulate the subsequent development of adaptive immunity and so may afford further therapeutic targets. Multiple challenges remain in developing human models of inflammatory resolution and in translating murine discoveries to date into drugs for humans. Anti-inflammatory treatments reduce inflammation but do not necessarily encourage resolution. Here, Fullerton and Gilroy suggest that some chronic inflammatory disorders may be characterized by an inability to resolve inflammation, and discuss the biology of resolution and translational efforts to target it. Dysregulated inflammation is a central pathological process in diverse disease states. Traditionally, therapeutic approaches have sought to modulate the pro- or anti-inflammatory limbs of inflammation, with mixed success. However, insight into the pathways by which inflammation is resolved has highlighted novel opportunities to pharmacologically manipulate these processes — a strategy that might represent a complementary (and perhaps even superior) therapeutic approach. This Review discusses the state of the art in the biology of resolution of inflammation, highlighting the opportunities and challenges for translational research in this field.