Immunosuppressive network promotes immunosenescence associated with aging and chronic inflammatory conditions

Abstract

The functional competence of the immune system gradually declines with aging, a process called immunosenescence. The age-related remodelling of the immune system affects both adaptive and innate immunity. In particular, a chronic low-grade inflammation, termed inflammaging, is associated with the aging process. Immunosenescence not only is present in inflammaging state, but it also occurs in several pathological conditions in conjunction with chronic inflammation. It is known that persistent inflammation stimulates a counteracting compensatory immunosuppression intended to protect host tissues. Inflammatory mediators enhance myelopoiesis and induce the generation of immature myeloid-derived suppressor cells (MDSC) which in mutual cooperation stimulates the immunosuppressive network. Immunosuppressive cells, especially MDSCs, regulatory T cells (Treg), and M2 macrophages produce immunosuppressive factors, e.g., TGF-β, IL-10, ROS, arginase-1 (ARG1), and indoleamine 2,3-dioxygenase (IDO), which suppress the functions of CD4/CD8T and B cells as well as macrophages, natural killer (NK) cells, and dendritic cells. The immunosuppressive armament (i) inhibits the development and proliferation of immune cells, (ii) decreases the cytotoxic activity of CD8T and NK cells, (iii) prevents antigen presentation and antibody production, and (iv) suppresses responsiveness to inflammatory mediators. These phenotypes are the hallmarks of immunosenescence. Immunosuppressive factors are able to control the chromatin landscape, and thus, it seems that the immunosenescence state is epigenetically regulated.

Immunosenescence and COVID-19

“…Thus, a relation between the proinflammatory Th17 lymphocytes and Tregs was demonstrated to change with advancing age and may depend on increased secretion of IL-6 ( Churov et al, 2020 , Deng et al, 2022 , Kimura and Kishimoto, 2010 , Mysliwska et al, 1998 , Mysliwska et al, 1997 , Salminen, 2021c , Schmitt et al, 2013 ). The data on the functionality of Tregs in aging individuals are conflicting; some papers indicate their increased immunosuppressive activities, other point at its reduction; it is noteworthy, that studies performed on mice may not correspond to the observations of Tregs in humans ( Churov et al, 2020 , Deng et al, 2022 , Guo et al, 2020 , Salminen, 2021b , Salminen, 2021c ).…”

“…The immunosenescence, understood as dysregulation and modified (reduced) function of the immune system in elderly, although even this definition may be questioned ( Pawelec et al, 2020 ) ( Pawelec et al, 2020 ), should not be confused with cellular senescence in general, although it does involve the senescence of the immune cells and in many facets the two processes are identical ( Salminen, 2021b ). Thus, cellular senescence consists of multiple phenotypic changes of long living (old) cells, including short telomeres, cessation of proliferation, enlarged size, acquisition of increased activity of the lysosomal acidic beta-galactosidase called the Senescence-Associated (SA)-βGal serving as biomarker of senescent cells regardless their tissue or organ of origin ( Blagosklonny, 2020 , Campbell et al, 2021 , Meftahi et al, 2020 , Wissler Gerdes et al, 2021 , Yao et al, 2020 ).…”

“…In fact, some researchers posit that in the case of macrophages the expression of p16 Ink4a is rather an indicator of their polarization; thus, ageing would lead to modification of the proportions (and so ratio) of proinflammatory M1 (decreasing), anti-inflammatory and pro-proliferative M2 (increasing) and other non-classical macrophages ( Hall et al, 2017 , Salminen, 2021a ). The M2 macrophages were also described to be regulatory (Mregs)/ immunosuppressive ( Salminen, 2021b ). This effect of aging on macrophages and the shifts of their populations was described for example in murine lungs which, if similar in humans, would likely participate in reduced clearance of respiratory tract-infecting viruses (including the SARS-CoV-2) and increased severity of COVID-19 in the old individuals ( Jackaman et al, 2013 , Wang et al, 2015 ).…”

“…Clear manifestations of the latter might be the increase of numbers of the myeloid-derived suppressor cells (MDSCs) in the blood of elderly people and mice ( Flores et al, 2017 , Grizzle et al, 2007 , Verschoor et al, 2013 ). There is likely a direct relation between inflammaging and the increase of MDSC; however, due to scarcity of different types of MDSC in human peripheral blood the data concerning this topic are scarce and so far limited and based on (successful) experiments where MDSC were induced from human monocytes in vitro by cocktail of proinflammatory cytokines ( Pawelec et al, 2021 , Salminen, 2021b , Veglia et al, 2018 ). This is clearly relevant for the interaction of aging organism with the SARS-CoV-2, as it was demonstrated that expansion of MDSC may inhibit the virus-specific T cells (especially cytotoxic cells) and predict fatal outcome of COVID-19 ( Agrati et al, 2020 , Bordoni et al, 2020 , Sacchi et al, 2020 ).…”

Tumorigenic Aspects of MSC Senescence—Implication in Cancer Development and Therapy

“…SASP factors support the generation of myeloid-derived suppressor cells (MDSC), and other immunosuppressive cells (regulatory T cells, M2 macrophages, tolerant dendritic cells, etc. ), leading to immunosenescence, and a perpetual loop of inflammaging and tissue degeneration is established [9].…”