A non-canonical type 2 immune response coordinates tuberculous granuloma formation and epithelialization

Cronan, Mark R.; Hughes, Erika J.; Brewer, W. Jared; Viswanathan, Gopinath; Hunt, Emily G.; Singh, Bindu; Mehra, Smriti; Oehlers, Stefan H.; Gregory, Simon; Kaushal, Deepak; Tobin, David M.

doi:10.1016/j.cell.2021.02.046

Cited by 67 publications

(72 citation statements)

References 85 publications

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“…In addition to cytokine levels, the macrophage polarization in vivo may be influenced by the growth factors, cell interactions, and environmental stressors. Despite the mutual antagonism of the macrophage polarization programs in vitro , recent studies demonstrated simultaneous presence of M1- and M2-like macrophages within TB lesions, where higher proportion of the M2-like Arginase-1-expressing macrophages was associated with the disease progression ( Cadena et al., 2017 ; Carow et al., 2019 ; Cronan et al., 2021 ). Spatial transcriptomic analysis and immunochemistry revealed that the M2-like macrophage markers were more abundant within the inner areas of TB granulomas ( Carow et al., 2019 ; Cadena et al., 2017 ), whereas the IFNγ-producing T cells were located mostly on the periphery of the organized granulomas ( Sakai et al., 2014 ).…”

Section: Introductionmentioning

confidence: 99%

Channeling macrophage polarization by rocaglates increases macrophage resistance to Mycobacterium tuberculosis

et al. 2021

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Summary Macrophages contribute to host immunity and tissue homeostasis via alternative activation programs. M1-like macrophages control intracellular bacterial pathogens and tumor progression. In contrast, M2-like macrophages shape reparative microenvironments that can be conducive for pathogen survival or tumor growth. An imbalance of these macrophages phenotypes may perpetuate sites of chronic unresolved inflammation, such as infectious granulomas and solid tumors. We have found that plant-derived and synthetic rocaglates sensitize macrophages to low concentrations of the M1-inducing cytokine IFN-gamma and inhibit their responsiveness to IL-4, a prototypical activator of the M2-like phenotype. Treatment of primary macrophages with rocaglates enhanced phagosome-lysosome fusion and control of intracellular mycobacteria. Thus, rocaglates represent a novel class of immunomodulators that can direct macrophage polarization toward the M1-like phenotype in complex microenvironments associated with hypofunction of type 1 and/or hyperactivation of type 2 immunity, e.g., chronic bacterial infections, allergies, and, possibly, certain tumors.

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Section: Introductionmentioning

confidence: 99%

Channeling macrophage polarization by rocaglates increases macrophage resistance to Mycobacterium tuberculosis

et al. 2021

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“…In an IL-13 overexpressing transgenic mouse, the infection with virulent M. tb resulted in the induction of Arg1+ macrophages and the formation of necrotic pulmonary granulomas driven by the arginase enzymatic activity (51). Similarly, the M2-like Arg1+ macrophage activation driving mycobacterial granuloma necrosis was observed in a zebrafish infected with M.marinum (17). The disease-promoting effects of Arg1+ macrophages in TB can be explained by arginine depletion and, thus, reducing NO production, a critical effector of host resistance to M.tb in mice (52).…”

Section: Discussionmentioning

confidence: 84%

“…Although typically found with the Th2 driven immune response to helminth infections, Arg1+ macrophages may have immunomodulatory or pro-fibrotic roles in mycobacterial granulomas (15,16). Recently, type 2 macrophage response was shown to contribute to the necrotization of mycobacterial granulomas in zebrafish model (17). However, current understanding of mechanisms that underlie the necrotization and organization of mycobacterial granulomas remains limited (18).…”

Section: Introductionmentioning

confidence: 99%

Dissemination and progression of pulmonaryMycobacterium aviuminfection in mouse model is associated with type 2 macrophage activation

Rosenbloom

Gavrish

Seidel

et al. 2021

Preprint

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Pulmonary infections caused by the group of nontuberculosis mycobacteria (NTM), Mycobacterium avium complex (MAC), are increasing worldwide and a growing public health concern. Pulmonary granulomas are the hallmark of MAC lung infection, yet reliable correlates of granuloma progression and susceptibility in immunocompetent hosts are poorly defined. The development of mouse models that recapitulate the diversity of granulomas seen in MAC pulmonary disease in humans is crucial to study mechanisms of susceptibility in humans and for preclinical evaluation of therapeutics. Unlike widely used inbred mouse strains, mice that carry the mutant allele at the genetic locus sst1 develop human-like pulmonary tuberculosis featuring well-organized caseating granulomas. These mice became instrumental in pre-clinical testing of novel interventions. In this study, we tested whether the B6.Sst1S that carries the sst1 mutant allele on standard B6 background develop more advanced pulmonary infection with NTM M. avium spp. hominissuis (M.av). To assess pulmonary disease progression, we utilized traditional semi-quantitative histomorphological evaluation and fluorescent multiplex immunohistochemistry (fmIHC) in combination with whole slide imaging and digital image analysis. After infection with the laboratory M.av strain 101, the B6.Sst1S pulmonary lesions progressed 12 to 20 weeks post infection, although we did not observe the formation of necrotic granulomas during this interval. Using fmIHC, we determined that the disease progression was associated with a steadily increasing proportion of mycobacteria infected Arg1+ and double positive iNOS+Arg1+ macrophages. The B6.Sst1S granulomas had a greater proportion of Arg1+ and double positive iNOS+Arg1+ macrophages, and decreased T cell density, as compared to wild type B6 mice. Thus, the genetic composition of the B6.Sst1S mice renders them more susceptible to pulmonary M.av infection. In combination with more virulent clinical isolates of M.av these mice could provide an improved mouse model that recapitulates more severe pulmonary disease in humans. The Arg1 macrophage expression in this model combined with automated fmIHC could serve as a sensitive biomarker for the unbiased assessment of medical countermeasures against NTM infection.

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“…Such cell-cell interactions could involve production of lipid mediators, as identified in our gene set enrichment analysis, and type II cytokines. In fact, a recent study in zebrafish showed that non-canonical type II immune IL-4 and IL-13 signals played critical roles in mycobacterial granuloma formation and macrophage epithelialization (Cronan et al, 2021). Additionally, our transcriptional profiling revealed changes in neuronal associated pathways raising the intriguing possibility that eosinophils may also interact with non-immune lung cells such as PNEC and airway sensory neurons.…”

Section: Resultsmentioning

confidence: 99%

Eosinophils are an integral component of the pulmonary granulocyte response in Tuberculosis and promote host resistance in mice

Carpenter

Castro

et al. 2021

Preprint

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Host resistance to Mycobacterium tuberculosis infection requires the activities of multiple leukocyte subsets, yet the roles of the different innate effector cells during tuberculosis are incompletely understood. Here we uncover an unexpected association between eosinophils and Mtb infection. In humans, eosinophils are decreased in the blood but enriched in resected human tuberculosis lung lesions and autopsy granulomas. Influx of eosinophils is also evident in infected zebrafish, mice, and nonhuman primate granulomas, where they are functionally activated and degranulate. Importantly, employing complementary genetic models of eosinophil deficiency, we demonstrate that, in mice, eosinophils are required for optimal pulmonary bacterial control and host survival after Mtb infection. Collectively, our findings uncover an unexpected recruitment of eosinophils to the infected lung tissue and a protective role for these cells in the control of Mtb infection in mice.

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A non-canonical type 2 immune response coordinates tuberculous granuloma formation and epithelialization

Cited by 67 publications

References 85 publications

Channeling macrophage polarization by rocaglates increases macrophage resistance to Mycobacterium tuberculosis

Channeling macrophage polarization by rocaglates increases macrophage resistance to Mycobacterium tuberculosis

Dissemination and progression of pulmonaryMycobacterium aviuminfection in mouse model is associated with type 2 macrophage activation

Eosinophils are an integral component of the pulmonary granulocyte response in Tuberculosis and promote host resistance in mice

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