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1.
Nat Commun ; 15(1): 4326, 2024 May 21.
Artigo em Inglês | MEDLINE | ID: mdl-38773113

RESUMO

Resolving inflammation is thought to return the affected tissue back to homoeostasis but recent evidence supports a non-linear model of resolution involving a phase of prolonged immune activity. Here we show that within days following resolution of Streptococcus pneumoniae-triggered lung inflammation, there is an influx of antigen specific lymphocytes with a memory and tissue-resident phenotype as well as macrophages bearing alveolar or interstitial phenotype. The transcriptome of these macrophages shows enrichment of genes associated with prostaglandin biosynthesis and genes that drive T cell chemotaxis and differentiation. Therapeutic depletion of post-resolution macrophages, inhibition of prostaglandin E2 (PGE2) synthesis or treatment with an EP4 antagonist, MF498, reduce numbers of lung CD4+/CD44+/CD62L+ and CD4+/CD44+/CD62L-/CD27+ T cells as well as their expression of the α-integrin, CD103. The T cells fail to reappear and reactivate upon secondary challenge for up to six weeks following primary infection. Concomitantly, EP4 antagonism through MF498 causes accumulation of lung macrophages and marked tissue fibrosis. Our study thus shows that PGE2 signalling, predominantly via EP4, plays an important role during the second wave of immune activity following resolution of inflammation. This secondary immune activation drives local tissue-resident T cell development while limiting tissue injury.


Assuntos
Dinoprostona , Modelos Animais de Doenças , Pulmão , Macrófagos , Camundongos Endogâmicos C57BL , Pneumonia Pneumocócica , Receptores de Prostaglandina E Subtipo EP4 , Streptococcus pneumoniae , Animais , Pneumonia Pneumocócica/imunologia , Pneumonia Pneumocócica/patologia , Pneumonia Pneumocócica/microbiologia , Pneumonia Pneumocócica/metabolismo , Camundongos , Dinoprostona/metabolismo , Streptococcus pneumoniae/imunologia , Receptores de Prostaglandina E Subtipo EP4/metabolismo , Receptores de Prostaglandina E Subtipo EP4/genética , Macrófagos/imunologia , Macrófagos/metabolismo , Pulmão/imunologia , Pulmão/patologia , Pulmão/microbiologia , Macrófagos Alveolares/imunologia , Macrófagos Alveolares/metabolismo , Cadeias alfa de Integrinas/metabolismo , Cadeias alfa de Integrinas/genética , Feminino , Antígenos CD/metabolismo , Antígenos CD/genética , Linfócitos T/imunologia
2.
Dev Cell ; 58(17): 1548-1561.e10, 2023 09 11.
Artigo em Inglês | MEDLINE | ID: mdl-37442140

RESUMO

Tumor-associated macrophages (TAMs) are a heterogeneous population of cells that facilitate cancer progression. However, our knowledge of the niches of individual TAM subsets and their development and function remain incomplete. Here, we describe a population of lymphatic vessel endothelial hyaluronan receptor-1 (LYVE-1)-expressing TAMs, which form coordinated multi-cellular "nest" structures that are heterogeneously distributed proximal to vasculature in tumors of a spontaneous murine model of breast cancer. We demonstrate that LYVE-1+ TAMs develop in response to IL-6, which induces their expression of the immune-suppressive enzyme heme oxygenase-1 and promotes a CCR5-dependent signaling axis, which guides their nest formation. Blocking the development of LYVE-1+ TAMs or their nest structures, using gene-targeted mice, results in an increase in CD8+ T cell recruitment to the tumor and enhanced response to chemotherapy. This study highlights an unappreciated collaboration of a TAM subset to form a coordinated niche linked to immune exclusion and resistance to anti-cancer therapy.


Assuntos
Neoplasias , Camundongos , Animais , Neoplasias/patologia , Macrófagos/metabolismo
3.
Trends Mol Med ; 25(3): 198-214, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30795972

RESUMO

Deciphering the origins of chronic inflammatory and autoimmune diseases remains elusive with reliance on therapies aimed at halting inflammation in its tracks. In recent years, an appreciation of targeting pathways by which inflammation is resolved has begun to rouse interest. Resolution of inflammation is driven by a complex set of mediators that regulate cellular events required to clear inflammatory cells from sites of infection or injury to restore tissue function. However, recent studies suggest that resolution is not the end of innate mediated immune responses to infection/injury. There is further immunological activity occurring after the resolution cascade is complete that alters the immune physiology of tissues, redefining what was once termed restorative homeostasis as adapted homeostasis.


Assuntos
Inflamação/etiologia , Inflamação/metabolismo , Doença Aguda , Animais , Biomarcadores , Doença Crônica , Citocinas/metabolismo , Suscetibilidade a Doenças , Humanos , Imunidade , Inflamação/tratamento farmacológico , Inflamação/patologia , Mediadores da Inflamação/metabolismo , Transdução de Sinais
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