Abstract
Accidental exposure to lethal doses of Gamma radiation leads to the systemic inflammatory syndrome which causes mortality. In view of this, management of hemopoietic syndrome by modulating pro-inflammatory response in clinically manageable time period seems to be the most appropriate strategy for encountering radiation induced damage and recovery. As both tissue and peripheral macrophages are critical for the management of radiation induced injuries, we have unraveled the immunomodulatory potential of radioprotective formulation (G-003M) on peripheral macrophages populations in this study. G-003M inhibited lethal radiation induced NO and Th1 effector cytokines in the exposed macrophages indicating its M1 dim polarizing capacity. In similar lines, conditioning of mice with G-003M before lethal irradiation (LR) inhibited LR induced titre of Th1 effector cytokines in both serums as well as in lung, small intestine, and spleen tissue confirming its immunomodulatory potential. G-003M potentially down modulated inflammatory response in LPS induced inflammatory model and enhanced M2 polarization of iNOS+ M1 effector macrophages providing a molecular hint on G-003M mechanism of action on macrophages. These observations revealed that G-003M potentially modulate pro-inflammatory programming of macrophages and mitigate radiation-induced inflammatory stress which is believed to contribute significantly to radioprotective attribute of G-003M. In this study, we demonstrate that Rutin and Podophyllotoxin drive M1dim/M2 polarization of LR primed macrophages apart from protecting DNA from radiation. These drugs have the capacity to programme innate immune cells like macrophages which may be involved in homeostasis during recovery.
Highlights
Immunosuppression, opportunistic infections and deleterious inflammation are the most important manifestations of exposure to high doses of low LET radiations [1]
In order to demonstrate the immune mediated mechanism of radioprotective formulations viz Rutin, Podophyllotoxin; we investigated the impact of these formulations on macrophages which are important for radioprotection
Our data revealed that these formulations upregulated the expression of CD206 and Arginase (M2 effector proteins) in both RAW and CD11b+ primary macrophages providing the evidence of M2 polarizing / scavenging capacity of Rutin and podophyllotoxinin macrophages which was in accordance of our original hypothesis
Summary
Immunosuppression, opportunistic infections and deleterious inflammation are the most important manifestations of exposure to high doses of low LET radiations [1]. These leads to hemopoietic and gastrointestinal syndrome which leads to the death of exposed individuals [2, 3]. G-003M is known to protect mice from respiratory syndrome and fibrosis by down regulating inflammatory response in mice [20]. On these bases, we anticipated that these formulations may reduce inflammatory response in the macrophages which may account for their radioprotective mechanism. We analyzed immunomodulatory role of G-003M on macrophages populations which are sentinels of inflammatory responses [21] and important for tissue homeostasis, host defense against tissue insult and infections [22,23,24]
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