Macrophages Are the Key Players in Promoting Hyper-Inflammatory Response in a Mouse Model of TB-IRIS

TB-IRIS is an abnormal inflammatory response in a subset of HIV-TB co-infected patients shortly after initiation of anti-retroviral therapy (ART). Therapy in these patients could have greatly improved the life expectancy as ART reconstitutes the function and number of CD4+ T cells and many patients...

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Autores principales:	Lalit Pal, Raj Nandani, Pawan Kumar, Bharati Swami, Gargi Roy, Sangeeta Bhaskar
Formato:	article
Lenguaje:	EN
Publicado:	Frontiers Media S.A. 2021
Materias:	TB-IRIS-tuberculosis-associated IRIS macrophage Mycobacterium tuberculosis inflammation HIV—human immunodeficiency virus Immunologic diseases. Allergy RC581-607
Acceso en línea:	https://doaj.org/article/7b9545933f0d4555a43193cdf7a2ec3f
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spelling	oai:doaj.org-article:7b9545933f0d4555a43193cdf7a2ec3f2021-12-01T08:18:14ZMacrophages Are the Key Players in Promoting Hyper-Inflammatory Response in a Mouse Model of TB-IRIS1664-322410.3389/fimmu.2021.775177https://doaj.org/article/7b9545933f0d4555a43193cdf7a2ec3f2021-11-01T00:00:00Zhttps://www.frontiersin.org/articles/10.3389/fimmu.2021.775177/fullhttps://doaj.org/toc/1664-3224TB-IRIS is an abnormal inflammatory response in a subset of HIV-TB co-infected patients shortly after initiation of anti-retroviral therapy (ART). Therapy in these patients could have greatly improved the life expectancy as ART reconstitutes the function and number of CD4+ T cells and many patients see improvement in symptoms but paradoxically up to 54% of co-infected patients develop TB-IRIS. Different studies have indicated that both innate and adaptive immunity are involved in the pathology of IRIS but the role of macrophages in abnormal activation of CD4+ T cells is poorly understood. Since macrophages are one of the major antigen-presenting cells and are infected by M.tb at a high frequency, they are very much likely to be involved in the development of TB-IRIS. In this study, we have developed a mouse model of experimental IRIS, in which M.tb-infected T-cell knockout mice undergo a fatal inflammatory disease after CD4+ T cell reconstitution. Lung macrophages and blood monocytes from M.tb-infected TCRβ−/− mice showed upregulated expression of cell surface activation markers and also showed higher mRNA expression of inflammation-associated chemokines and matrix metalloproteases responsible for tissue damage. Furthermore, cytokine and TLR signaling feedback mechanism to control excessive inflammation was also found to be dysregulated in these macrophages under lymphopenic conditions. Previous studies have shown that hyperactive CD4+ T cells are responsible for disease induction and our study shows that somehow macrophages are in a higher activated state when infected with M.tb in an immune-deficient condition, which results in excessive activation of the adoptively transferred CD4+ T cells. Understanding of the mechanisms underlying the pathophysiology of TB-IRIS would facilitate identification of prospective biomarkers for disease development in HIV-TB co-infected patients before starting antiretroviral therapy.Lalit PalRaj NandaniPawan KumarBharati SwamiGargi RoySangeeta BhaskarFrontiers Media S.A.articleTB-IRIS-tuberculosis-associated IRISmacrophageMycobacterium tuberculosisinflammationHIV—human immunodeficiency virusImmunologic diseases. AllergyRC581-607ENFrontiers in Immunology, Vol 12 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	TB-IRIS-tuberculosis-associated IRIS macrophage Mycobacterium tuberculosis inflammation HIV—human immunodeficiency virus Immunologic diseases. Allergy RC581-607
spellingShingle	TB-IRIS-tuberculosis-associated IRIS macrophage Mycobacterium tuberculosis inflammation HIV—human immunodeficiency virus Immunologic diseases. Allergy RC581-607 Lalit Pal Raj Nandani Pawan Kumar Bharati Swami Gargi Roy Sangeeta Bhaskar Macrophages Are the Key Players in Promoting Hyper-Inflammatory Response in a Mouse Model of TB-IRIS
description	TB-IRIS is an abnormal inflammatory response in a subset of HIV-TB co-infected patients shortly after initiation of anti-retroviral therapy (ART). Therapy in these patients could have greatly improved the life expectancy as ART reconstitutes the function and number of CD4+ T cells and many patients see improvement in symptoms but paradoxically up to 54% of co-infected patients develop TB-IRIS. Different studies have indicated that both innate and adaptive immunity are involved in the pathology of IRIS but the role of macrophages in abnormal activation of CD4+ T cells is poorly understood. Since macrophages are one of the major antigen-presenting cells and are infected by M.tb at a high frequency, they are very much likely to be involved in the development of TB-IRIS. In this study, we have developed a mouse model of experimental IRIS, in which M.tb-infected T-cell knockout mice undergo a fatal inflammatory disease after CD4+ T cell reconstitution. Lung macrophages and blood monocytes from M.tb-infected TCRβ−/− mice showed upregulated expression of cell surface activation markers and also showed higher mRNA expression of inflammation-associated chemokines and matrix metalloproteases responsible for tissue damage. Furthermore, cytokine and TLR signaling feedback mechanism to control excessive inflammation was also found to be dysregulated in these macrophages under lymphopenic conditions. Previous studies have shown that hyperactive CD4+ T cells are responsible for disease induction and our study shows that somehow macrophages are in a higher activated state when infected with M.tb in an immune-deficient condition, which results in excessive activation of the adoptively transferred CD4+ T cells. Understanding of the mechanisms underlying the pathophysiology of TB-IRIS would facilitate identification of prospective biomarkers for disease development in HIV-TB co-infected patients before starting antiretroviral therapy.
format	article
author	Lalit Pal Raj Nandani Pawan Kumar Bharati Swami Gargi Roy Sangeeta Bhaskar
author_facet	Lalit Pal Raj Nandani Pawan Kumar Bharati Swami Gargi Roy Sangeeta Bhaskar
author_sort	Lalit Pal
title	Macrophages Are the Key Players in Promoting Hyper-Inflammatory Response in a Mouse Model of TB-IRIS
title_short	Macrophages Are the Key Players in Promoting Hyper-Inflammatory Response in a Mouse Model of TB-IRIS
title_full	Macrophages Are the Key Players in Promoting Hyper-Inflammatory Response in a Mouse Model of TB-IRIS
title_fullStr	Macrophages Are the Key Players in Promoting Hyper-Inflammatory Response in a Mouse Model of TB-IRIS
title_full_unstemmed	Macrophages Are the Key Players in Promoting Hyper-Inflammatory Response in a Mouse Model of TB-IRIS
title_sort	macrophages are the key players in promoting hyper-inflammatory response in a mouse model of tb-iris
publisher	Frontiers Media S.A.
publishDate	2021
url	https://doaj.org/article/7b9545933f0d4555a43193cdf7a2ec3f
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Macrophages Are the Key Players in Promoting Hyper-Inflammatory Response in a Mouse Model of TB-IRIS

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