Losartan inhibits conventional dendritic cell maturation and Th1 and Th17 polarization responses: Νovel mechanisms of preventive effects on lipopolysaccharide-induced acute lung injury

Abstract

Abstract. Acute lung injury (ALI) remains one of major causes of morbidity and mortality in intensive care medicine. The lack of efficient pharmacological interventions contributes to the high mortality rate of ALI. Losartan, an antagonist of angiotensin II (Ang II) type 1 receptor, is a potent therapeutic drug for ALI. Recent reports suggest that losartan inhibits the maturation of dendritic cells (DCs), impairs T-helper (Th) 1 immune response and ultimately attenuates inflammation in several Ang II-mediated inflammatory diseases. However, the possible protective mechanisms of losartan in ALI remain poorly understood. This study was aimed to define the effect of losartan on the frequency and phenotype of respiratory conventional DCs (cDCs) and Th cells polarization in lipopolysaccharide (LPS)-induced ALI mice. Results demonstrate that early after induction of LPS-induced ALI, cDCs expressing modest amounts of CD80 rapidly accumulated in the lungs. In addition, polarized Th1 and Th17 responses were markedly increased in LPS-induced ALI mice at 24 and 48 h. Of note, losartan led to inhibition of respiratory cDCs maturation at 6 h and suppressed Th1 and Th17 polarization responses compared with ALI mice at 24 and 48 h. Collectively, our findings may provide a novel and, at least, partial explanation for the protective effects by which losartan inhibits lung cDCs maturation and suppresses Th1 and Th17 immune responses.

Angiotensin II type-1 receptor (AT1R) regulates expansion, differentiation, and functional capacity of antigen-specific CD8+ T cells

“…Our group and others have shown that Ang II plays a pivotal role in regulating the T cell response in an autocrine or paracrine manner via AT 1 R, which is upregulated in activated T cells10111213141521. In addition, other studies show that different innate immune cells, such as monocytes, macrophages, and dendritic cells, produce Ang II and express higher levels of mRNA of the different renin-angiotensin system (RAS) components than T cells8101617181920. During the encounter with the antigen, in the context of co-stimulatory stimuli, Ang II activates AT 1 R in T cells initiating distinct transcriptional profiles that regulate avidity by antigen, activation, clonal expansion, migration and effector function101112131415161718192021.…”

“…Although Ang II binds 2 different receptors, AT 1 R and AT 2 R, previous studies have shown that AT 1 R expression is upregulated in T cells in vitro and during Plasmodium berghei ANKA (PbA) infection and mediates most of the effects of Ang II in T cells56789101112131415182021. The upregulated AT 1 R plays a role in activation, effector function, CD8 + T-cell sequestration in the brain, cerebral edema, and behavioral impairment during the blood stage of PbA infection, as well as in other models of diseases1011131518192021. However, the specific role of AT 1 R expressed by antigen-specific CD8 + T cells in regulating their response is not yet clear yet.…”

“…Our group and others have focused on describing the role of RAS effector molecules, especially angiotensin II (Ang II) and its receptor AT 1 (AT 1 R), in the regulation of adaptive immune response56789101112131415161718192021. Ang II has been proposed to have pro-inflammatory effects, via AT 1 R8910111213151617181920, however the cellular mechanisms underlying the role of AT 1 R in the regulation of antigen-specific T cells in different pathologies are not clear yet.…”

“…It has been demonstrated that T cells possess a functional RAS and are capable of producing Ang II10111213142021. In these cells, Ang II promotes proliferation, differentiation, effector function, adhesion, migration, and acts as a co-stimulatory molecule important to T-cell activation, and all these effects are mediated by AT 1 R binding56791011121314152021.…”

“…In these cells, Ang II promotes proliferation, differentiation, effector function, adhesion, migration, and acts as a co-stimulatory molecule important to T-cell activation, and all these effects are mediated by AT 1 R binding56791011121314152021. Importantly, AT 1 R expression is upregulated in T cells during activation in vitro and in vivo , for instance during the blood stage of Plasmodium berghei ANKA (PbA) infection, strengthening the importance of this receptor for T-cell response11121315.…”