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Inflammation is a host defense response to various invading stimuli, but an excessive and persistent inflammatory response can cause tissue injury, which can lead to irreversible organ damage and dysfunction. Excessive inflammatory responses are believed to link to most human diseases. A specific type of leukocyte infiltration into invaded tissues is required for inflammation. Historically, the underlying molecular mechanisms of this process during inflammation were an enigma, compromising research in the fields of inflammation, immunology, and pathology. However, the pioneering discovery of chemotactic cytokines (chemokines), monocyte-derived neutrophil chemotactic factor (MDNCF; interleukin [IL]-8, CXCL8) and monocyte chemotactic and activating factor (MCAF; monocyte chemotactic factor 1 [MCP-1], CCL2) in the late 1980s finally enabled us to address this issue. In this review, we provide a historical overview of chemokine research over the last 35 years.

Interleukin (IL)-11 is a member of the IL-6 family of cytokines and is involved in multiple cellular responses, including tumor development. However, the origin and functions of IL-11-producing (IL-11 + ) cells are not fully understood. To characterize IL-11 + cells in vivo, we generate Il11 reporter mice. IL-11 + cells appear in the colon in murine tumor and acute colitis models. Il11ra1 or Il11 deletion attenuates the development of colitis-associated colorectal cancer. IL-11 + cells express fibroblast markers and genes associated with cell proliferation and tissue repair. IL-11 induces the activation of colonic fibroblasts and epithelial cells through phosphorylation of STAT3. Human cancer database analysis reveals that the expression of genes enriched in IL-11 + fibroblasts is elevated in human colorectal cancer and correlated with reduced recurrence-free survival. IL-11 + fibroblasts activate both tumor cells and fibroblasts via secretion of IL-11, thereby constituting a feed-forward loop between tumor cells and fibroblasts in the tumor microenvironment. The stromal fibroblast population in the colon is composed of heterogeneous and distinct cell subtypes that play a crucial role in the development of colitis and colon cancer. Here the authors generate IL-11 reporter mice and characterize the origin and phenotype of inflammatory IL-11 + fibroblasts in colitis and colon cancer preclinical models.

CD8 + T cells are the key effector cells that contribute to the antitumor immune response. They comprise various T-cell clones with diverse antigen-specific T-cell receptors (TCRs). Thus, elucidating the overall antitumor responses of diverse T-cell clones is an emerging challenge in tumor immunology. With the recent advancement in next-generation DNA sequencers, comprehensive analysis of the collection of TCR genes (TCR repertoire analysis) is feasible and has been used to investigate the clonal responses of antitumor T cells. However, the immunopathological significance of TCR repertoire indices is still undefined. In this review, we introduce two approaches that facilitate an immunological interpretation of the TCR repertoire data: inter-organ clone tracking analysis and single-cell TCR sequencing. These approaches for TCR repertoire analysis will provide a more accurate understanding of the response of tumor-specific T cells in the tumor microenvironment.

This study identifies 17 strains of human-derived Clostridia capable of inducing the accumulation and functional maturation of regulatory T cells; it is suggested that these strains may be useful candidates for the future development of oral bacterial therapeutics to treat human inflammatory disorders. Bacterial cocktail settles the stomach Imbalances of the gut microbiota significantly contribute to inflammatory and allergic states, and therefore the manipulation of gut microbes holds promise for treating these immune disorders. This paper reports the isolation of 17 strains of human-derived Clostridia capable of stimulating the immune response by inducing the accumulation and functional maturation of regulatory T cells. Oral administration of a cocktail of these Clostridia attenuates disease in mouse models of colitis and allergic diarrhoea, suggesting that these strains may be candidates for the development of oral bacterial therapeutics to treat inflammatory disorders. Manipulation of the gut microbiota holds great promise for the treatment of inflammatory and allergic diseases 1 , 2 . Although numerous probiotic microorganisms have been identified 3 , there remains a compelling need to discover organisms that elicit more robust therapeutic responses, are compatible with the host, and can affect a specific arm of the host immune system in a well-controlled, physiological manner. Here we use a rational approach to isolate CD4 + FOXP3 + regulatory T (T reg )-cell-inducing bacterial strains from the human indigenous microbiota. Starting with a healthy human faecal sample, a sequence of selection steps was applied to obtain mice colonized with human microbiota enriched in T reg -cell-inducing species. From these mice, we isolated and selected 17 strains of bacteria on the basis of their high potency in enhancing T reg cell abundance and inducing important anti-inflammatory molecules—including interleukin-10 (IL-) and inducible T-cell co-stimulator (ICOS)—in T reg cells upon inoculation into germ-free mice. Genome sequencing revealed that the 17 strains fall within clusters IV, XIVa and XVIII of Clostridia, which lack prominent toxins and virulence factors. The 17 strains act as a community to provide bacterial antigens and a TGF-β-rich environment to help expansion and differentiation of T reg cells. Oral administration of the combination of 17 strains to adult mice attenuated disease in models of colitis and allergic diarrhoea. Use of the isolated strains may allow for tailored therapeutic manipulation of human immune disorders.

Liver fibrosis results from chronic liver injury triggered by factors such as viral infection, excess alcohol intake, and lipid accumulation. However, the mechanisms underlying liver fibrosis are not fully understood. Here, we demonstrate that the expression of fibroblast growth factor 18 ( Fgf18 ) is elevated in mouse livers following the induction of chronic liver fibrosis models. Deletion of Fgf18 in hepatocytes attenuates liver fibrosis; conversely, overexpression of Fgf18 promotes liver fibrosis. Single-cell RNA sequencing reveals that overexpression of Fgf18 in hepatocytes results in an increase in the number of Lrat + hepatic stellate cells (HSCs), thereby inducing fibrosis. Mechanistically, FGF18 stimulates the proliferation of HSCs by inducing the expression of Ccnd1 . Moreover, the expression of FGF18 is correlated with the expression of profibrotic genes, such as COL1A1 and ACTA2 , in human liver biopsy samples. Thus, FGF18 promotes liver fibrosis and could serve as a therapeutic target to treat liver fibrosis. Fibroblast growth factor (FGF)18 plays pleiotropic roles, including bone development and carcinogenesis, however, its precise role in liver fibrosis remains incompletely understood. Here, the authors show that FGF18 promotes liver fibrosis by stimulating hepatic stellate cell proliferation, without concomitant upregulation of profibrotic genes.

Myeloid cells such as monocytes and monocyte-derived macrophages promote tumor progression. Recent reports suggest that extramedullary hematopoiesis sustains a sizable reservoir of tumor-infiltrating monocytes in the spleen. However, the influence of the spleen on tumor development and the extent to which spleen monocytes populate the tumor relative to bone marrow (BM) monocytes remain controversial. Here, we used mice expressing the photoconvertible protein Kikume Green-Red to track the redistribution of monocytes from the BM and spleen, and mice expressing fluorescent ubiquitination-based cell-cycle indicator proteins to monitor active hematopoiesis in these tissues. In mice bearing late-stage tumors, the BM, besides being the major site of monocyte production, supplied the expansion of the spleen reservoir, replacing 9% of spleen monocytes every hour. Deployment of monocytes was equally rapid from the BM and the spleen. However, BM monocytes were younger than those in the spleen and were 2.7 times more likely to migrate into the tumor from the circulation. Partly as a result of this intrinsic difference in migration potential, spleen monocytes made only a minor contribution to the tumor-infiltrating monocyte population. At least 27% of tumor monocytes had traveled from the BM in the last 24 h, compared with only 2% from the spleen. These observations highlight the importance of the BM as the primary hematopoietic tissue and monocyte reservoir in tumor-bearing mice, despite the changes that occur in the spleen monocyte reservoir during tumor development.

Cigarette smoke (CS) exposure reportedly enhances allergic airway inflammation. However, some studies have shown an association between current cigarette smoke exposure and a low risk for allergic rhinitis. Thus, the impact of CS exposure on allergic rhinitis remains poorly understood. The purpose of this study was to investigate the effects of CS on the respiratory mucosa (RM) and the olfactory epithelium (OE) of mice with allergic rhinitis, as the effects may differ depending on the nasal histological compartments. Eight-week-old male BALB/c mice were used for this study. We developed a mouse model of smoking by intranasally administering 10 doses of a CS solution (CSS), and a mouse model of allergic rhinitis by sensitization with intraperitoneal ovalbumin (OVA) injection and intranasal challenge with OVA. We examined the effects of CS on the nasal RM and OE in mice with or without allergic rhinitis using histological, serum, and genetic analyses. First, we examine whether CSS exposure induces allergic responses and then, examined allergic responses in the OVA-sensitized allergic rhinitis mice with or without CSS exposure. Short-term CSS administration intensified allergic responses including increased infiltration of eosinophils and inflammatory cells and upregulation of interleukin-5 expression in the nasal RM of OVA-immunized mice, although only CSS induced neither allergic responses nor impairment of the RM and OE. Notably, repetitive OVA-immunization partially impaired the OE in the upper-lateral area, but CSS administration did not reinforce this impairment in OVA-induced allergic mice. Short-term CSS exposure strengthened allergic responses in the nasal RM and did not change the structure of the OE. These results suggest that patients with allergic rhinitis could experience exacerbation of allergic symptoms after CS exposure.

Abstract Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive, and irreversible interstitial pneumonia caused by the excessive production and deposition of extracellular matrix components, including type I collagen. Activated fibroblasts, called α-SMA (α-smooth muscle actin)-expressing myofibroblasts, are the major source of type I collagen in pulmonary fibrosis (PF), but the mechanisms underlying disease progression have not been fully elucidated. Here, we obtained lung fibroblasts from patients with IPF from both nonfibrotic and fibrotic areas as determined by a lung computed tomography scan and compared gene expression between these areas by DNA microarray. We found that ANGPTL4 (angiopoietin-like 4) was highly expressed only in fibroblasts from the fibrotic area. ANGPTL4 was selectively expressed in the fibroblastic area of IPF lungs, where the myofibroblast marker α-SMA was also expressed. ANGPTL4 also regulates the gene expression of fibrosis-related markers, cell migration, and proliferation. In addition, ANGPTL4 expression in a murine model of PF induced by treatment with bleomycin was significantly induced in the lungs from the acute to the chronic phase. Single-cell transcriptome analysis during the course of bleomycin-induced PF revealed that Angptl4 was predominantly expressed in the activated fibroblasts and myofibroblasts. Moreover, the administration of recombinant ANGPTL4 to the bleomycin-induced fibrosis model significantly increased collagen deposition and exacerbated the PF. In contrast, the pathogenesis of PF in Angptl4-deficient mice was improved. These results indicate that ANGPTL4 is critical for the progression of PF and might be an early diagnostic marker and therapeutic target for IPF.

Effective cancer immunotherapy relies on the clonal proliferation and expansion of CD8 + T cells in the tumor. However, our insights into clonal expansions are limited, owing to an inability to track the same clones in tumors over time. Here, we develop a multi-site tumor mouse model system to track hundreds of expanding and contracting CD8 + T cell clones over multiple timepoints in tumors of the same individual. Through coupling of clonal expansion dynamics and single-cell RNA/TCR-seq data, we identify a transcriptomic signature in PD-1 + Ly108 + precursor exhausted cells that strongly predicts rates of intratumoral clone expansion. The signature correlates with expansion in mice, both with and without immunotherapies, and in patients undergoing PD-1 blockade therapy. Expression of the signature during treatment corresponds with positive clinical outcomes. Downregulation of the signature precedes clone contraction—a phase in which clones contract but maintain revivable precursor exhausted cells in the tumor. LAG-3 blockade re-activates the expansion signature, re-expanding pre-existing clones, including previously contracted clones. These findings reveal how the study of clonal expansion dynamics provide a powerful ‘pan-immunotherapy’ signature for monitoring immunotherapies with implications for their future development. Effective response to immune checkpoint inhibitors depends on the proliferation and expansion of tumor-reactive CD8 +  T cells. By combining analysis of CD8 +  T cell clones in a preclinical multi-site tumor model with clinical datasets, the authors track the expansion dynamics of hundreds of T cell clones over time and define a signature to predict intratumoral CD8 +  T cell expansion in response to immunotherapies.

This protocol describes an optimized procedure for retroviral (RV) transduction of mouse T cells by enriching RV-susceptible activated CD8 + T cells through Percoll density centrifugation, enhancing the frequency of RV-transduced cells ∼sixfold in vivo . Retroviral (RV) expression of genes of interest (GOIs) is an invaluable tool and has formed the foundation of cellular engineering for adoptive cell therapy in cancer and other diseases. However, monitoring of transduced T cells long term (weeks to months) in vivo remains challenging because of the low frequency and often poor durability of transduced T cells over time when transferred without enrichment. Traditional methods often require additional overnight in vitro culture after transduction. Moreover, in vitro -generated effector CD8 + T cells enriched by sorting often have reduced viability, making it difficult to monitor the fate of transferred cells in vivo . Here, we describe an optimized mouse CD8 + T-cell RV transduction protocol that uses simple and rapid Percoll density centrifugation to enrich RV-susceptible activated CD8 + T cells. Percoll density centrifugation is simple, can be done on the day of transduction, requires minimal time, has low reagent costs and improves cell recovery (up to 60%), as well as the frequency of RV-transduced cells (∼sixfold over several weeks in vivo as compared with traditional methods). We have used this protocol to assess the long-term stability of CD8 + T cells after RV transduction by comparing the durability of T cells transduced with retroviruses expressing each of six commonly used RV reporter genes. Thus, we provide an optimized enrichment and transduction approach that allows long-term in vivo assessment of RV-transduced T cells. The overall procedure from T-cell isolation to RV transduction takes 2 d, and enrichment of activated T cells can be done in 1 h.